Fused tricyclic compound, preparation method therefor and pharmaceutical use thereof

Abstract

Provided are a fused tricyclic compound, a preparation method therefor and a pharmaceutical use thereof. Specifically, provided are a compound as shown in general formula (I), a preparation method therefor, a pharmaceutical composition containing the compound, and a use thereof as a therapeutic agent, particularly a use as an RAS inhibitor and a use in the preparation of a drug for treating and / or preventing RAS-mediated or RAS-dependent diseases or disorders. The groups in general formula (I) are as defined in the description.

Description

A fused tricyclic compound, its preparation method and its pharmaceutical application Technical Field

[0001] This disclosure pertains to the pharmaceutical field and relates to a fused tricyclic compound of general formula (I), a method for its preparation, a pharmaceutical composition containing the compound, and its use as a therapeutic agent, particularly as a RAS inhibitor and in the preparation of medicaments for the treatment and / or prevention of diseases or conditions mediated or dependent on RAS mutant proteins. Background Technology

[0002] RAS (Rapid Adenosine Reproductive Genes) are among the most common oncogenes in tumors, accounting for approximately 30% of tumors, and include KRAS, HRAS, and NRAS. The most frequently mutated sites in RAS are codons 12, 13, and 61, with codon 12 mutations being the most common. Under normal conditions, RAS proteins switch between a GDP-binding inactive state and a GTP-binding activated state. Mutations in RAS disrupt the activity of GTPase-activating proteins (GAPs)-dependent or endogenous GTP hydrolases, thus keeping the RAS protein in a persistently activated GTP-binding state. This continuously activates downstream signaling pathways such as MAPK and PI3K, promoting tumor development and progression.

[0003] Because the RAS protein lacks traditional small molecule binding sites and has a pM affinity for GTP, making it extremely difficult to inhibit with compounds, RAS has long been considered an untreatable drug target. Although KRAS G12C inhibitors are already on the market, drugs that directly target the GTP-bound activated state of RAS have not yet been approved. Therefore, there is still a need to develop such inhibitors for the treatment of RAS-mutant tumors. Summary of the Invention

[0004] The purpose of this disclosure is to provide a compound of general formula (I) or a pharmaceutically acceptable salt thereof.

[0005] in:

[0006] X and Y may be the same or different, and each is independently selected from (CR). 4a R 4b ) m NR 5 (CR 4c R 4d ) r’ C(O)NR 5 NR 5 C(O), C(O) and O(CR) 4e R 4f )n’ ;

[0007] m can be 0, 1, 2, 3, or 4;

[0008] n' can be 0, 1, 2, 3 or 4;

[0009] r' can be 0, 1, 2, 3 or 4;

[0010] R 4a R 4b R 4c R 4d R 4e and R 4f They may be the same or different, and each is independently selected from hydrogen atoms or R. 4aa ;

[0011] Each R 4aa The same or different, and each independently selected from halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, cyano, amino, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are optionally substituted by one or more R*; or two R* groups. 4aa Together with the attached atoms, it forms cycloalkyl, heterocyclic, aryl, or heteroaryl groups, or R 4aa R D Together with the attached atom, it forms a cycloalkyl or heterocyclic group, wherein the cycloalkyl, heterocyclic, aryl or heteroaryl group is optionally substituted by one or more R*;

[0012] R 5 R d and R R The same or different, and each independently selected from hydrogen atom, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkylalkyl, heterocyclic alkyl, arylalkyl, heteroarylalkyl, cycloalkylenyl, heterocyclic alkenyl, aryl alkenyl, heteroaryl alkenyl, cycloalkylynyl, heterocyclic ynylynyl, arylynylynyl, and heteroarylynyl, wherein the alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkylalkyl, heterocyclic alkyl, arylalkyl, heteroarylalkyl, cycloalkylenyl, heterocyclic alkenyl, aryl alkenyl, heteroaryl alkenyl, cycloalkylynyl, heterocyclic ynylynyl, arylynylynyl, and heteroarylynyl are each independently optionally selected from halogen, oxo, =S, =NR. 64 Alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, -NR 9a R 9bThe alkyl group is substituted with one or more of the following: hydroxyl, hydroxyalkyl, cycloalkyl optionally substituted with one or more R*, heterocyclic group optionally substituted with one or more R*, aryl group optionally substituted with one or more R*, heteroaryl group optionally substituted with one or more R*, cycloalkylalkyl optionally substituted with one or more R*, heterocyclic alkyl optionally substituted with one or more R*, arylalkyl optionally substituted with one or more R*, and heteroarylalkyl optionally substituted with one or more R*; or

[0013] R 4a R 4b R 4c R 4d R 4e R 4f and R 5 The two atoms in the group together with the attached atoms form a cycloalkyl, heterocyclic, aryl, or heteroaryl group, wherein the cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally substituted by one or more R*.

[0014] G 1 G 2 G 3 and G 4 One of them is a carbon atom attached to ring B, and the other three are the same or different, and each is independently CH, CR 6 Or N;

[0015] Ring A is a heterocyclic group;

[0016] Ring B and ring C may be the same or different, and each is independently selected from cycloalkyl, heterocyclic, aryl or heteroaryl groups;

[0017] R A R B R C R D and R 6 They may be the same or different, and each is independently selected from halogen, alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, -NR 7a R 7b -NR 7a OR 7b -ONR 7a R 7b -NR 7c NR 7a R 7b hydroxyl group, -C(O)R 8 -C(O)OR 8 -C(O)NR 7a R 7b -S(O) w R 8, Oxide group, =S, =NOR 61 =CR 62 R 63 =NR 64 Cycloalkyl, heterocyclic, aryl, and heteroaryl, wherein the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each independently and optionally selected from halogen, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, -NR 9a R 9b The substance is substituted by one or more substituents selected from hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl; or

[0018] Two Rs A Together with the attached atoms, it forms a cycloalkyl, heterocyclic, aryl, or heteroaryl group, wherein the cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally surrounded by one or more R groups. AA Replace; or

[0019] Two Rs D Together with the attached atoms, it forms cycloalkyl, heterocyclic, aryl, or heteroaryl groups, or R D R d The atoms bonded together form a heterocyclic group, wherein the cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally bonded by one or more R groups. DD replace;

[0020] R 2 Selected from O, NH and N-alkyl;

[0021] L 2 The alkylene group is optionally alkylene oxide (R0) or alkylene oxide (R0) by one or more R0. L2 replace;

[0022] R L2 Same or different, and each independently selected from halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, cyano, amino, hydroxy, hydroxyalkyl, oxo, =S, =NOR 61 =CR 62 R 63 =NR 64 Cycloalkyl, heterocyclic, aryl, and heteroaryl groups, wherein the alkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are optionally substituted with one or more R* groups; or

[0023] Two Rs L2 Together with the attached atoms, it forms a cycloalkyl, heterocyclic, aryl, or heteroaryl group, wherein the cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally surrounded by one or more R groups. LL2 replace;

[0024] L 1It is an alkylene or cycloalkyl group, wherein the alkylene or cycloalkyl group is optionally surrounded by one or more R groups. L1 replace;

[0025] L is R 10 or

[0026] R 11 and R 12 The same or different, and each independently selected from hydrogen atoms, halogens, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, cyano, amino, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are optionally separated by one or more R E replace;

[0027] L 3 For key or -N(R) L3 )C(O)-;

[0028] L 4 For bonds or -(alkylene) y -N(R L4 )C(=O)-;

[0029] R 10 Selected from alkyl, cycloalkyl, heterocyclic and NR 101 R 102 The alkyl, cycloalkyl, and heterocyclic groups are each independently and optionally influenced by one or more R groups. F replace;

[0030] Each R F They may be the same or different, and each is independently selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, -NR 7a R 7b hydroxyl group, oxo group, =S, =NOR 61 =CR 62 R 63 =NR 64 cycloalkyl, heterocyclic, aryl, heteroaryl, -C(O)R F1 -C(O)OR F1 -C(O)NR F2 R F3 -S(O) w R F1 and -S(O) w OR F1 The alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each independently and optionally converted by one or more R groups. FF replace;

[0031] R61 R 62 R 63 and R 64 The same or different, and each independently selected from hydrogen atoms, halogens, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, hydroxyl, hydroxyalkyl, and cycloalkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, and heterocyclic groups are each independently optionally selected by one or more R # Replace; or

[0032] R 63 R 62 Together with the attached atoms, they form cycloalkyl or heterocyclic groups, each of which is optionally independently bound by one or more R groups. FF replace;

[0033] R 7a R 7b R 7c R 9a R 9b R L3 R L4 R 101 R 102 R F2 and R F3 They may be the same or different, and each is independently selected from hydrogen atoms, alkyl, heteroalkyl, hydroxyalkyl, aminoalkyl, cycloalkyl and heterocyclic groups, wherein each of the alkyl, cycloalkyl and heterocyclic groups is independently optionally substituted by one or more substituents selected from halogen, alkyl, alkoxy, haloalkyl and haloalkoxy;

[0034] Or R 7a and R 7b It forms a heterocyclic group together with the attached nitrogen atom, or R 9a and R 9b It forms a heterocyclic group together with the attached nitrogen atom, or R 101 and R 102 It forms a heterocyclic group together with the attached nitrogen atom, or R F2 and R F3 Together with the attached nitrogen atom, a heterocyclic group is formed, wherein the heterocyclic group is optionally substituted by one or more substituents selected from halogen, oxo, =S, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0035] R 8 and R F1 The same or different, and each independently selected from hydrogen atoms, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, cycloalkyl, and heterocyclic groups, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, and heterocyclic groups are each independently optionally selected by one or more R atoms.# replace;

[0036] Each R*, R AA R DD R LL2 R L1 R E R FF and R # The same or different, and each independently selected from oxo, =S, =N-alkyl, =NH, halogen, alkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, cyano, alkylthio, amino, -NHalkyl, -N(alkyl)2, -alkylene-amino, -alkylene-NHalkyl, -alkylene-N(alkyl)2, amide, nitro, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkylalkyl, heterocyclic alkyl, arylalkyl, heteroarylalkyl, cycloalkyloxy, heterocyclic oxy, aryloxy, and heteroaryloxy, wherein the =N-alkyl, alkyl, alkenyl, alkoxy, alkoxyalkyl, alkoxyalkyl, alkylthio, -NHalkyl, -N(alkyl)2, -alkylene-amino, -alkylene-NHalkyl, -alkylene The alkyl-N(alkyl)2, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkylalkyl, heterocyclicalkyl, arylalkyl, heteroarylalkyl, cycloalkyloxy, heterocyclicoxy, aryloxy and heteroaryloxy are each independently and optionally substituted by one or more substituents selected from oxo, =S, halogen, alkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, cyano, alkylthio, amino, -NHalkyl, -N(alkyl)2, -alkylene-amino, -alkylene-NHalkyl, -alkylene-N(alkyl)2, amide, nitro, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkylalkyl, heterocyclicalkyl, arylalkyl, heteroarylalkyl, cycloalkyloxy, heterocyclicoxy, aryloxy and heteroaryloxy;

[0037] w is 0, 1, or 2;

[0038] n is 0, 1, 2, 3, 4, 5, or 6;

[0039] p is 0, 1, 2, 3, 4, 5 or 6;

[0040] q can be 0, 1, 2, 3, 4, 5, or 6;

[0041] r is 0, 1, 2, 3, 4, 5, or 6; and

[0042] y can be 0, 1, 2, 3, 4, 5 or 6.

[0043] This disclosure provides a compound of general formula (I) or a pharmaceutically acceptable salt thereof.

[0044] in:

[0045] X and Y may be the same or different, and each is independently selected from (CR). 4a R 4b ) m NR 5 (CR 4c R 4d ) r’ C(O)NR 5 NR 5 C(O), C(O) and O(CR) 4e R 4f ) n’ ;

[0046] m can be 0, 1, 2, 3, or 4;

[0047] n' can be 0, 1, 2, 3 or 4;

[0048] r' can be 0, 1, 2, 3 or 4;

[0049] R 4a R 4b R 4c R 4d R 4e and R 4f They may be the same or different, and each is independently selected from hydrogen atoms or R. 4aa ;

[0050] Each R 4aa The same or different, and each independently selected from halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, cyano, amino, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are optionally substituted by one or more R*; or two R* groups. 4aa Together with the attached atoms, it forms cycloalkyl, heterocyclic, aryl, or heteroaryl groups, or R 4aa R D Together with the attached atom, it forms a cycloalkyl or heterocyclic group, wherein the cycloalkyl, heterocyclic, aryl or heteroaryl group is optionally substituted by one or more R*;

[0051] R 5 R d and R R The same or different, and each independently selected from hydrogen atoms, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups, wherein the cycloalkyl, heterocyclic, aryl, and heteroaryl groups are optionally substituted by one or more R*; or

[0052] R 4a R 4b R4c R 4d R 4e R 4f and R 5 The two atoms in the group together with the attached atoms form a cycloalkyl, heterocyclic, aryl, or heteroaryl group, wherein the cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally substituted by one or more R*.

[0053] G 1 G 2 G 3 and G 4 One of them is a carbon atom attached to ring B, and the other three are the same or different, and each is independently CH, CR 6 Or N;

[0054] Ring A is a heterocyclic group;

[0055] Ring B and ring C may be the same or different, and each is independently selected from cycloalkyl, heterocyclic, aryl or heteroaryl groups;

[0056] R A R B R C R D and R 6 They may be the same or different, and each is independently selected from halogen, alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, -NR 7a R 7b -NR 7a OR 7b -ONR 7a R 7b -NR 7c NR 7a R 7b hydroxyl group, -C(O)R 8 -C(O)OR 8 -C(O)NR 7a R 7b -S(O) w R 8 , Oxide group, =S, =NOR 61 =CR 62 R 63 =NR 64 Cycloalkyl, heterocyclic, aryl, and heteroaryl, wherein the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each independently and optionally selected from halogen, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, -NR 9a R 9b The substance is substituted by one or more substituents selected from hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl; or

[0057] Two Rs A Together with the attached atoms, it forms a cycloalkyl, heterocyclic, aryl, or heteroaryl group, wherein the cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally surrounded by one or more R groups. AA Replace; or

[0058] Two Rs D Together with the attached atoms, it forms cycloalkyl, heterocyclic, aryl, or heteroaryl groups, or R D R d The atoms bonded together form a heterocyclic group, wherein the cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally bonded by one or more R groups. DD replace;

[0059] R 2 Selected from O, NH and N-alkyl;

[0060] L 2 The alkylene group is optionally alkylene oxide (R0) or alkylene oxide (R0) by one or more R0. L2 replace;

[0061] R L2 Same or different, and each independently selected from halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, cyano, amino, hydroxy, hydroxyalkyl, oxo, =S, =NOR 61 =CR 62 R 63 =NR 64 Cycloalkyl, heterocyclic, aryl, and heteroaryl groups, wherein the alkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are optionally substituted with one or more R* groups; or

[0062] Two Rs L2 Together with the attached atoms, it forms a cycloalkyl, heterocyclic, aryl, or heteroaryl group, wherein the cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally surrounded by one or more R groups. LL2 replace;

[0063] L 1 It is an alkylene or cycloalkyl group, wherein the alkylene or cycloalkyl group is optionally surrounded by one or more R groups. L1 replace;

[0064] L is R 10 or

[0065] R 11 and R 12The same or different, and each independently selected from hydrogen atoms, halogens, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, cyano, amino, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are optionally separated by one or more R E replace;

[0066] L 3 For key or -N(R) L3 )C(O)-;

[0067] L 4 For bonds or -(alkylene) y -N(R L4 )C(=O)-;

[0068] R 10 Selected from alkyl, cycloalkyl, heterocyclic and NR 101 R 102 The alkyl, cycloalkyl, and heterocyclic groups are each independently and optionally influenced by one or more R groups. F replace;

[0069] Each R F They may be the same or different, and each is independently selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, -NR 7a R 7b hydroxyl group, oxo group, =S, =NOR 61 =CR 62 R 63 =NR 64 cycloalkyl, heterocyclic, aryl, heteroaryl, -C(O)R F1 -C(O)OR F1 -C(O)NR F2 R F3 -S(O) w R F1 and -S(O) w OR F1 The alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each independently and optionally converted by one or more R groups. FF replace;

[0070] R 61 R 62 R 63 and R 64 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, alkyl groups, haloalkyl groups, hydroxyalkyl groups, and cycloalkyl groups; or

[0071] R 63 R 62Together with the attached atoms, they form cycloalkyl or heterocyclic groups, each of which is optionally independently bound by one or more R groups. FF replace;

[0072] R 7a R 7b R 7c R 9a R 9b R L3 R L4 R 101 R 102 R F2 and R F3 They may be the same or different, and each is independently selected from hydrogen atoms, alkyl, heteroalkyl, hydroxyalkyl, aminoalkyl, cycloalkyl and heterocyclic groups, wherein each of the alkyl, cycloalkyl and heterocyclic groups is independently optionally substituted by one or more substituents selected from halogen, alkyl, alkoxy, haloalkyl and haloalkoxy;

[0073] Or R 7a and R 7b It forms a heterocyclic group together with the attached nitrogen atom, or R 9a and R 9b It forms a heterocyclic group together with the attached nitrogen atom, or R 101 and R 102 It forms a heterocyclic group together with the attached nitrogen atom, or R F2 and R F3 Together with the attached nitrogen atom, a heterocyclic group is formed, wherein the heterocyclic group is optionally substituted by one or more substituents selected from halogen, oxo, =S, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0074] R 8 and R F1 The same or different, and each independently selected from hydrogen atoms, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, cycloalkyl, and heterocyclic groups, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, and heterocyclic groups are each independently optionally selected by one or more R atoms. # replace;

[0075] Each R*, R AA R DD R LL2 R L1 R E R FF and R #They may be the same or different, and each is independently selected from oxo, =S, halogen, alkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, cyano, alkylthio, amino, -NHalkyl, -N(alkyl)2, -alkylene-amino, -alkylene-NHalkyl, -alkylene-N(alkyl)2, amide, nitro, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkylalkyl, heterocyclic alkyl, arylalkyl, heteroarylalkyl, cycloalkyloxy, heterocyclic oxy, aryloxy, and heteroaryloxy;

[0076] w is 0, 1, or 2;

[0077] n is 0, 1, 2, 3, 4, 5, or 6;

[0078] p is 0, 1, 2, 3, 4, 5 or 6;

[0079] q can be 0, 1, 2, 3, 4, 5, or 6;

[0080] r can be 0, 1, 2, 3, 4, 5, or 6;

[0081] y can be 0, 1, 2, 3, 4, 5 or 6.

[0082] In some embodiments of this disclosure, ring B is a fused bicyclic ring; in some embodiments, ring B is selected from 5-membered heteroaryl-5-membered heteroaryl, 5-membered heteroaryl-phenyl, 5-membered heteroaryl-6-membered heteroaryl, 6-membered heteroaryl-phenyl, 6-membered heteroaryl-6-membered heteroaryl, and naphthyl; in some embodiments, ring B is 5-membered heteroaryl-phenyl; in some embodiments, ring B is indole; in some embodiments, ring B is... In some implementation schemes, ring B is *End is connected to ring C, end With L 2 Connected.

[0083] In some embodiments disclosed herein, R 2 It is O.

[0084] In some embodiments disclosed herein, R R It is a hydrogen atom or a carbon atom. 1-6 Alkyl; in some embodiments, R R It is a hydrogen atom.

[0085] In some embodiments of this disclosure, ring A is a 5- to 8-membered heterocyclic group; in some embodiments, ring A is a 6-membered heterocyclic group.

[0086] In some embodiments disclosed herein, each R B They may be the same or different, and each is independently selected from halogens, C 1-6 Alkyl, C 1-6Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyl alkyl, cyano, 3- to 8-membered cycloalkyl, or 3- to 8-membered heterocyclic group; in some embodiments, R B C 1-6 Alkyl; in some embodiments, R B For ethyl; in some embodiments, R B For halogen; in some implementations, R B For F; in some implementations, R B C 1-6 Halogenated alkyl; in some embodiments, R B It is CH2CF3.

[0087] In some embodiments of this disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof is a compound represented by general formula (IIL) or a pharmaceutically acceptable salt thereof.

[0088] in:

[0089] Dashed lines indicate single or double bonds;

[0090] R B1 R B2 R B3 and R B4 They may be the same or different, and each is independently selected from hydrogen atoms or R. B ;

[0091] L 1 R B G 1 G 2 G 3 G 4 X, Y, R D ,r,R d L 2 R A , n, ring C, R C p and L are as defined in general formula (I).

[0092] In some embodiments of this disclosure, the compounds represented by general formulas (I) and (III) or their pharmaceutically acceptable salts are compounds represented by general formula (II) or their pharmaceutically acceptable salts.

[0093] in:

[0094] Dashed lines indicate single or double bonds;

[0095] R B1 R B2 RB3 and R B4 They may be the same or different, and each is independently selected from hydrogen atoms or R. B ;

[0096] R B G 1 G 2 G 3 G 4 X, Y, R D ,r,R d L 2 R A , n, ring C, R C p and L are as defined in general formula (I).

[0097] In some embodiments of this disclosure, X is (CR 4a R 4b ) m Or C(O); where R 4a R 4b And m is as defined in general formula (I); in some embodiments, X is selected from single bond, CH2, CH2CH2 and C(O); in some embodiments, X is selected from single bond or CH2.

[0098] In some embodiments of this disclosure, Y is O(CR) 4e R 4f ) n’ or NR 5 (CR 4c R 4d ) r’ ;where R 4c R 4d R 4e R 4f R 5 , n' and r' are as defined in general formula (I); in some embodiments, Y is selected from O, OCH2, NH and NCH3; in some embodiments, Y is OCH2.

[0099] In some embodiments of this disclosure, XY is selected from (CH2). m OCH2, OCH2CH2, NHC(O), NHCH2, N(CH3)CH2, m is 0, 1, or 2. The end is connected to the piperazine ring; in some embodiments, XY is selected from OCH2, CH2OCH2, OCH2CH2, NHC(O), NHCH2 and N(CH3)CH2; in some embodiments, XY is OCH2 or CH2OCH2.

[0100] In some embodiments disclosed herein, RD Selected from halogens, C 1-6 Alkyl, C 1-6 Haloalkyl; or two R atoms on the same atom D Together with the attached atoms, they form 3- to 6-membered cycloalkyl groups (i.e., spirocyclic rings); or two R atoms on adjacent atoms D Together with the attached atoms, they form 3- to 6-membered cycloalkyl groups or 3- to 6-membered heterocyclic groups (i.e., fused rings); or two R atoms on two non-adjacent atoms. D Together they form C 1-6 Alkylene (i.e., bridged ring); or R D With R d Together with the attached atoms, it forms a 3- to 6-membered heterocyclic group (i.e., a fused ring); in some embodiments, R D Selected from halogens, C 1-6 Alkyl, C 1-6 Haloalkyl; or two R atoms on the same atom D Together with the attached atom, it forms a cyclopropyl group.

[0101] In some embodiments of this disclosure, r is 0, 1, or 2; in other embodiments, r is 0.

[0102] In some embodiments of this disclosure, ring C is selected from phenyl, 5- or 6-membered heterocyclic groups, and 5- or 6-membered heteroaryl groups; in some embodiments, ring C is phenyl or 5- or 6-membered heteroaryl; in some embodiments, ring C is a 6-membered heterocyclic group; in some embodiments, ring C is morpholino; in some embodiments, ring C is thiazolyl or morpholino; in some embodiments, ring C is... In some implementations, ring C is In some embodiments, ring C is a 5-membered heteroaryl group; in some embodiments, ring C is phenyl or thiazolyl; in some embodiments, ring C is thiazolyl, thiophene, furanyl, oxazolyl, pyrazolyl, and imidazolyl; in some embodiments, ring C is thiazolyl; in some embodiments, ring C is... In some implementations, ring C is In some implementations, ring C is The *terminus is connected to a ring B (in general formula I) or a phenyl group (in general formulas II and IIL). End and L 1 (in general formula I and IIL) or CH2 (in general formula II) connected together.

[0103] In some embodiments disclosed herein, L 2 C 1-6 Alkylene; in some embodiments, L 2 For optional C 1-6 Alkyl-substituted propylene; in some embodiments, L2 It is CH2C(CH3)2CH2.

[0104] In some embodiments disclosed herein, L 2 C 1-6 Alkylene, the C 1-6 Alkylenes are optionally subjected to one or more R L2 Replace, two R L2 Together with the attached atoms, it forms a 3- to 6-membered cycloalkyl group or a 3- to 6-membered heterocyclic group; in some embodiments, L 2 For being two R L2 Substituted propylidene, two R L2 Together with the attached atoms, it forms a 3- to 6-membered cycloalkyl group; in some embodiments, L 2 For being two R L2 Substituted propylidene, two R L2 Together with the attached atom, it forms a cyclopropyl group; in some embodiments, L 2 for In some implementations, L 2 for In some implementations, L 2 for End and R 2 (In general formula I) or O (in general formula II, IIL) is connected, and the * end is connected to ring B (in general formula I) or pyrrole ring (in general formula II, IIL).

[0105] In some embodiments disclosed herein, G 4 It is a carbon atom and is attached to a ring B (in general formula I) or a pyrrole ring (in general formulas II and III), G 1 G 2 and G 3 They may be the same or different, and each is independently selected from N, CH and CR. 6 R 6 As defined in general formula (I); in some implementations, G 3 It is a carbon atom and is attached to a ring B or a pyrrole ring, G 1 G 2 and G 4 They may be the same or different, and each is independently selected from N, CH and CR. 6 R 6 As defined in general formula (I); in some implementations, G 4 It is a carbon atom and is attached to a ring B or a pyrrole ring, G 1 For N, G 2 For CH, G 3 For CR 6 R 6 C 1-6 Alkoxy C1-6 alkyl.

[0106] In some embodiments of this disclosure, the compound represented by general formula (I) or (IIL) or a pharmaceutically acceptable salt thereof is a compound represented by general formula (IIIL) or a pharmaceutically acceptable salt thereof.

[0107] in:

[0108] R C1 Selected from hydrogen atoms or R C ;

[0109] R 6A Selected from hydrogen atoms or R 6 ;

[0110] m is 0, 1, or 2;

[0111] m1 is 0, 1, 2, 3, 4, 5 or 6;

[0112] L 1 R B1 R B2 R B3 R B4 R 4aa R 6 G 1 R d R A n, R C And L is as defined in general formula (II).

[0113] The purpose of this disclosure is to provide a compound of general formula (IV) or a pharmaceutically acceptable salt thereof.

[0114] m, m1, L 1 R B1 R B2 R B3 R B4 R 4aa R 6A R C1 G 1 R A , n and L are as defined in general formula (IIIL).

[0115] In some embodiments disclosed herein, L 1 For CH2; in some implementations, L 1 It is CH2 or a 3- to 6-membered cycloalkyl group; in some embodiments, L 1 It is CH2 or cyclopropyl; in some embodiments, L 1 It is cyclopropyl; in some embodiments, L 1 for In some implementations, L 1 CH2 or

[0116] In some embodiments of this disclosure, the compound represented by general formula (I), (IIL), (IIIL) or (II), or a pharmaceutically acceptable salt thereof, is a compound represented by general formula (III) or a pharmaceutically acceptable salt thereof.

[0117] in:

[0118] R C1 Selected from hydrogen atoms or R C ;

[0119] R 6A Selected from hydrogen atoms or R 6 ;

[0120] m is 0, 1, or 2;

[0121] m1 is 0, 1, 2, 3, 4, 5 or 6;

[0122] R B1 R B2 R B3 R B4 R 4aa R 6 G 1 R d R A n, R C And L is as defined in general formula (II).

[0123] In some implementation schemes disclosed herein, for Where X, Y, G 1 G 2 G 3 R D r and R d As defined in general formula (I).

[0124] In some implementation schemes disclosed herein, for Among them G 1 R 6A R 4aa m1, m and R d As defined in general formula (III).

[0125] In some implementation schemes disclosed herein, for Among them G 1 R 6A R 4aa m1 and m are as defined in general formula (III).

[0126] In some implementation schemes disclosed herein, for Among them G 1 R 6A and R d As defined in general formula (III); in some implementations, G 1 For N, R 6A C 1-6 Alkoxy C 1-6 Alkyl, R d It is a hydrogen atom or a carbon atom. 1-6 Alkyl; in some embodiments, G 1 For N, R 6A C 1-6 Alkoxy C 1-6 Alkyl, R d Selected from hydrogen atoms, C 1-6 Alkyl, 3- to 6-membered cycloalkyl, 3- to 6-membered heterocyclic, 3- to 6-membered cycloalkyl C 1-6 Alkyl, 3 to 6-membered heterocyclic C 1-6 Alkyl, 3- to 6-membered cycloalkyl C 2-6 alkynyl, 3 to 6-membered heterocyclic C 2-6 alkynyl group; in some implementations, G 1 For N, R 6A C 1-6 Alkoxy C 1-6 Alkyl, R d Selected from methyl, cyclopropyl, In some embodiments of this disclosure, m is 0 or 1; in some embodiments, m is 0; and in some embodiments, m is 1.

[0127] In some embodiments disclosed herein, each R 4aa They may be the same or different, and each is independently selected from halogens, C 1-6 Alkyl or C 1-6 Haloalkyl; or two R atoms on the same atom 4aa The atoms attached together form a 3- to 6-membered cycloalkyl group; in some embodiments, two R atoms on the same atom 4aa The atoms bonded together form a cyclopropyl group; in some embodiments, R 4aa They may be the same or different, and each is independently selected from halogens, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups.

[0128] In some embodiments of this disclosure, m1 is 0, 1, or 2; in some embodiments, m1 is 2; and in some embodiments, m1 is 0.

[0129] In some implementation schemes disclosed herein, Selected from Where R A and n are as defined in general formula (I); in some implementations, for Where R A and n are as defined in general formula (I); in some implementations, for In some implementation schemes, for

[0130] In some implementation schemes disclosed herein, Selected from Where R A and n are as defined in general formula (II); in some implementations, n is... In some implementation schemes, for

[0131] In some embodiments disclosed herein, R 6A Selected from hydrogen atoms, halogens, C 1-6 Alkyl, 2- to 6-membered heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 alkoxy, cyano, amino, hydroxy, 3- to 8-membered cycloalkyl, 3- to 8-membered heterocyclic, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl, wherein the C 1-6 Alkyl, 2- to 6-membered heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 The alkoxy, 3- to 8-membered cycloalkyl, 3- to 8-membered heterocyclic, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl groups are each independently selected from halogens, oxo groups, C... 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, cyano, hydroxyl and C 1-6 One or more substituents in the hydroxyalkyl group are substituted; in some embodiments, R 6A Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Alkoxy, wherein the C 1-6Alkyl, C 1-6 Each alkoxy group is independently selected from halogens, C... 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 One or more substituents in the haloalkoxy group are substituted; in some embodiments, R 6A C 1-6 Alkoxy C 1-6 Alkyl; in some embodiments, R 6A For CH3OCH(CH3); in some implementations, R 6A for In some implementation schemes, R 6A for

[0132] In some embodiments disclosed herein, R 6 Selected from halogens, C 1-6 Alkyl, 2- to 6-membered heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 alkoxy, cyano, amino, hydroxy, 3- to 8-membered cycloalkyl, 3- to 8-membered heterocyclic, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl, wherein the C 1-6 Alkyl, 2- to 6-membered heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 The alkoxy, 3- to 8-membered cycloalkyl, 3- to 8-membered heterocyclic, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl groups are each independently selected from halogens, oxo groups, C... 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, cyano, hydroxyl and C 1-6 One or more substituents in the hydroxyalkyl group are substituted; in some embodiments, R 6 Selected from halogens, C 1-6 Alkyl and C 1-6 Alkoxy, wherein the C 1-6 Alkyl, C 1-6 Each alkoxy group is independently selected from halogens, C... 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 One or more substituents in the haloalkoxy group are substituted; in some embodiments, R 6 C 1-6 Alkoxy C 1-6 Alkyl; in some embodiments, R 6For CH3OCH(CH3); in some implementations, R 6 for In some implementation schemes, R 6 for

[0133] In some embodiments disclosed herein, G 1 For N or CH; in some implementations, G 1 Let N be the number of elements in the array.

[0134] In some embodiments disclosed herein, R d Selected from hydrogen atoms, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, 3- to 8-membered cycloalkyl, and 3- to 8-membered heterocyclic groups; in some embodiments, R d It is a hydrogen atom or a carbon atom. 1-6 Alkyl; in some embodiments, R d For methyl; in some embodiments, R d Selected from hydrogen atoms, C 1-6 Alkyl, 3- to 6-membered cycloalkyl, 3- to 6-membered heterocyclic, 3- to 6-membered cycloalkyl C 1-6 Alkyl, 3 to 6-membered heterocyclic C 1-6 Alkyl, 3- to 6-membered cycloalkyl C 2-6 alkynyl, 3 to 6-membered heterocyclic C 2-6 alkynyl group; in some implementations, R d Selected from methyl, cyclopropyl, In some implementation schemes, R d Selected from methyl, cyclopropyl and In some implementation schemes, R d Selected from hydrogen atom, methyl or cyclopropyl; in some embodiments, R d Selected from methyl or cyclopropyl; in some embodiments, R d It is a methyl group.

[0135] In some embodiments disclosed herein, R B1 Selected from hydrogen atoms, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, 3- to 8-membered cycloalkyl, and 3- to 8-membered heterocyclic groups; in some embodiments, R B1 Selected from hydrogen atoms, C 1-6 Alkyl and C 1-6 Halogenated alkyl; in some embodiments, R B1 It is a hydrogen atom or a carbon atom. 1-6 Alkyl; in some embodiments, R B1 C 1-6Halogenated alkyl; in some embodiments, R B1 For CH2CF3; in some implementations, R B1 It is an ethyl group.

[0136] In some embodiments disclosed herein, R B2 R B3 and R B4 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyl alkyl, cyano, 3- to 8-membered cycloalkyl, or 3- to 8-membered heterocyclic group; in some embodiments, R B2 R B3 and R B4 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl and cyano groups; in some embodiments, R B2 R B3 and R B4 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl and C 1-6 Halogenated alkyl; in some embodiments, R B2 R B3 and R B4 They may be the same or different, and each is independently selected from hydrogen atoms or halogens.

[0137] In some embodiments disclosed herein, R B2 It is a hydrogen atom or a halogen; in some implementations, R B2 For hydrogen atoms; in some implementations, R B2 For halogen; in some implementations, R B2 It is F.

[0138] In some embodiments disclosed herein, R B3 It is a hydrogen atom or a halogen; in some implementations, R B3 For hydrogen atoms; in some implementations, R B3 For halogen; in some implementations, R B3 It is F.

[0139] In some embodiments disclosed herein, R B4 It is a hydrogen atom or a halogen; in some implementations, R B4For hydrogen atoms; in some implementations, R B4 For halogen; in some implementations, R B4 It is F.

[0140] In some embodiments disclosed herein, R C1 Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyl alkyl, cyano, 3- to 8-membered cycloalkyl, or 3- to 8-membered heterocyclic group; in some embodiments, R C1 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl; in some embodiments, R C1 It is a hydrogen atom.

[0141] In some embodiments disclosed herein, R C Selected from halogens, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyl alkyl, cyano, 3- to 8-membered cycloalkyl, or 3- to 8-membered heterocyclic group; in some embodiments, R C Selected from halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups.

[0142] In some embodiments of this disclosure, p is 0, 1, or 2; in some embodiments, p is 0 or 1; and in some embodiments, p is 0.

[0143] In some embodiments disclosed herein, R A They may be the same or different, and each is independently selected from halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyl and cyano groups, or two R groups on the same atom A Or two R atoms on different atoms A Together with the attached atoms, it forms a 3- to 8-membered cycloalkyl or 3- to 8-membered heterocyclic group, wherein the 3- to 8-membered cycloalkyl or 3- to 8-membered heterocyclic group is optionally reacted with one or more halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyl and cyano substitution; in some embodiments, R A They may be the same or different, and each is independently a halogen or a carbon. 1-6 Alkyl; in some embodiments, R AThey may be the same or different, and each is independently F or methyl.

[0144] In some embodiments of this disclosure, n is 0, 1, 2 or 3; in some embodiments, n is 0; in some embodiments, n is 2.

[0145] In some embodiments disclosed herein, L is Ring W 1 For optional use by one or more R F Substituted nitrogen-containing heterocyclic group, ring W 2 It is a cycloalkyl or heterocyclic group, R W3 For hydrogen atoms or R # w4 is 0, 1, 2, 3 or 4, R F R # R 11 and R 12 As defined in general formula (I); in some implementations, L or for In some implementations, L or for

[0146] In some embodiments disclosed herein, ring W 1 It is a 3- to 12-membered nitrogen-containing heterocyclic group; in some embodiments, the ring W 1 for *Ended carbonyl group; in some embodiments, W 1 for * The carbonyl group is attached to the end.

[0147] In some embodiments disclosed herein, ring W 2 It is a 3- to 12-membered heterocyclic group; in some embodiments, the ring W 2 It is a 3- to 6-membered heterocyclic group; in some embodiments, the ring W 2 for *End-connected carbonyl group; in some embodiments, the ring W 2 for

[0148] In some embodiments disclosed herein, R W3 Selected from hydrogen atom, oxo group, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, hydroxyl, C 1-6 Hydroxyalkyl, cyano, amino, -NH C 1-6 Alkyl, -N(C) 1-6alkyl)2 and 3 to 6-membered cycloalkyl; in some embodiments, R W3 Selected from hydrogen atom, oxo group, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and 3- to 6-membered cycloalkyl groups; in some embodiments, R W3 Selected from hydrogen atom, oxo group, C 1-6 Alkyl and 3- to 6-membered cycloalkyl; in some embodiments, R W3 Selected from oxo, methyl, and cyclopropyl groups; in some embodiments, R W3 Selected from methyl and cyclopropyl.

[0149] In some embodiments of this disclosure, w4 is 0, 1, or 2; in some embodiments, w4 is 2.

[0150] In some embodiments of this disclosure, L is a 3- to 8-membered cycloalkyl group, wherein the 3- to 8-membered cycloalkyl group is optionally coated with one or more halogens, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, =CR 62 R 63 C 1-6 Haloalkyl, C 1-6 Hydroxyl and cyano substitution, R 62 and R 63 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl; in some embodiments, L is selected from... In some implementation schemes, L is selected from In some implementation schemes, L is selected from In some implementation schemes, L is selected from In some implementation schemes, L is selected from In some implementations, L is In some implementations, L is In some implementations, L is In some implementations, L is In some implementations, L is In some implementations, L is

[0151] In some embodiments disclosed herein, R 11 C 1-6 Alkyl or 3- to 8-membered cycloalkyl; in some embodiments, R11 It is isopropyl or cyclopentyl.

[0152] In some embodiments disclosed herein, R 12 It is a hydrogen atom.

[0153] In some embodiments disclosed herein, L 3 It is a bond or -N(CH3)C(O)-.

[0154] In some embodiments disclosed herein, R L3 It can be a hydrogen atom or a methyl group.

[0155] In some embodiments disclosed herein, L 4 For key.

[0156] In some embodiments disclosed herein, R L4 It can be a hydrogen atom or a methyl group.

[0157] In some embodiments of this disclosure, y is 0 or 1; in other embodiments, y is 0.

[0158] In some embodiments disclosed herein, R 10 Selected from 3- to 12-membered cycloalkyl groups, 3- to 12-membered heterocyclic groups, and N(C) groups. 1-6 Alkyl)2, wherein the 3- to 12-membered cycloalkyl group or the 3- to 12-membered heterocyclic group is optionally surrounded by one or more R F Replace, R F As defined in general formula (I); in some implementations, R 10 Selected from 3- to 12-membered cycloalkyl groups, 3- to 12-membered heterocyclic groups, and N(C) groups. 1-6 Alkyl)2, wherein the 3- to 12-membered cycloalkyl group or the 3- to 12-membered heterocyclic group is optionally surrounded by one or more R F Replace, R F Selected from halogens, C 1-6 Alkyl and -C(O)R F1 R F1 Selected from C 2-6 alkenyl, C 2-6 Alkyne group and 3 to 8-membered heterocyclic group, the C 2-6 alkenyl, C 2-6 The alkynyl group and the 3 to 8-membered heterocyclic group are optionally separated by one or more R groups. # Replace, R # Selected from halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl, amino, -NHC 1-6 Alkyl, -N(C) 1-6 Alkyl) 2- and 3- to 8-membered cycloalkyl.

[0159] In some embodiments of this disclosure, the compound represented by general formula (II) or a pharmaceutically acceptable salt thereof, wherein XY is OCH2 or CH2OCH2; G 4 It is a carbon atom attached to a pyrrole ring, G 1 G 2 and G 3 They may be the same or different, and each is independently selected from N, CH and CR. 6 R 6 Selected from halogens, C 1-6 Alkyl and C 1-6 Alkoxy, wherein the C 1-6 Alkyl, C 1-6 Each alkoxy group is independently selected from halogens, C... 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 One or more substituents in the haloalkoxy group are substituted; r is 0; R d It is a hydrogen atom or a carbon atom. 1-6 Alkyl; R B1 It is a hydrogen atom or a carbon atom. 1-6 Alkyl; R B2 R B3 and R B4 Whether the same or different, and each independently selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl and cyano groups; L 2 For optional C 1-6 Alkyl-substituted propylene group; ring C is thiazolyl; R C Selected from halogens, C 1-6 Alkyl and C 1-6 Haloalkyl; p is 0 or 1; for R A Halogen or C 1-6 Alkyl; n is 0 or 1; L is

[0160] In some embodiments of this disclosure, the compound represented by the general formula (IIL) or a pharmaceutically acceptable salt thereof, wherein L 1 It is CH2 or cyclopropyl; XY is OCH2 or CH2OCH2; G 4 It is a carbon atom attached to a pyrrole ring, G 1 G 2 and G 3 They may be the same or different, and each is independently selected from N, CH and CR.6 R 6 Selected from halogens, C 1-6 Alkyl and C 1-6 Alkoxy, wherein the C 1-6 Alkyl, C 1-6 Each alkoxy group is independently selected from halogens, C... 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 One or more substituents in the haloalkoxy group are substituted; r is 0; R d Selected from hydrogen atoms, C 1-6 Alkyl, 3- to 6-membered cycloalkyl, 3- to 6-membered heterocyclic, 3- to 6-membered cycloalkyl C 1-6 Alkyl, 3 to 6-membered heterocyclic C 1-6 Alkyl, 3- to 6-membered cycloalkyl C 2-6 alkynyl, 3 to 6-membered heterocyclic C 2-6 alkynyl group; R B1 It is a hydrogen atom or a carbon atom. 1-6 Alkyl; R B2 R B3 and R B4 Whether the same or different, and each independently selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl and cyano groups; L 2 For optional C 1-6 Alkyl-substituted propylene group; ring C is thiazolyl; R C Selected from halogens, C 1-6 Alkyl and C 1-6 Haloalkyl; p is 0 or 1; for R A Halogen or C 1-6 Alkyl; n is 0 or 1; L is

[0161] In some embodiments of this disclosure, the compound represented by the general formula (IIL) or a pharmaceutically acceptable salt thereof, wherein L 1 It is CH2 or cyclopropyl; XY is OCH2 or CH2OCH2; G 4 It is a carbon atom attached to a pyrrole ring, G 1 G 2 and G 3 They may be the same or different, and each is independently selected from N, CH and CR. 6 R 6 Selected from halogens, C1-6 Alkyl and C 1-6 Alkoxy, wherein the C 1-6 Alkyl, C 1-6 Each alkoxy group is independently selected from halogens, C... 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 One or more substituents in the haloalkoxy group are substituted; r is 0; R d Selected from hydrogen atoms, C 1-6 Alkyl, 3- to 6-membered cycloalkyl, 3- to 6-membered heterocyclic, 3- to 6-membered cycloalkyl C 1-6 Alkyl, 3 to 6-membered heterocyclic C 1-6 Alkyl, 3- to 6-membered cycloalkyl C 2-6 alkynyl, 3 to 6-membered heterocyclic C 2-6 alkynyl group; R B1 Selected from hydrogen atoms, C 1-6 Alkyl and C 1-6 Halogenated alkyl; R B2 R B3 and R B4 Whether the same or different, and each independently selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl and cyano groups; L 2 For optional C 1-6 Alkyl-substituted propylene; ring C is thiazolyl or morpholino; R C Selected from halogens, C 1-6 Alkyl and C 1-6 Haloalkyl; p is 0 or 1; for R A Halogen or C 1-6 Alkyl; n is 0 or 1; L is

[0162] In some embodiments of this disclosure, the compound represented by the general formula (IIL) or a pharmaceutically acceptable salt thereof, wherein L 1 It is CH2 or cyclopropyl; XY is OCH2 or CH2OCH2; G 4 It is a carbon atom attached to a pyrrole ring, G 1 G 2 and G 3 They may be the same or different, and each is independently selected from N, CH and CR. 6 R 6 Selected from halogens, C 1-6 Alkyl and C 1-6Alkoxy, wherein the C 1-6 Alkyl, C 1-6 Each alkoxy group is independently selected from halogens, C... 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 One or more substituents in the haloalkoxy group are substituted; r is 0; R d Selected from hydrogen atoms, C 1-6 Alkyl, 3- to 6-membered cycloalkyl, 3- to 6-membered heterocyclic, 3- to 6-membered cycloalkyl C 1-6 Alkyl, 3 to 6-membered heterocyclic C 1-6 Alkyl, 3- to 6-membered cycloalkyl C 2-6 alkynyl, 3 to 6-membered heterocyclic C 2-6 alkynyl group; R B1 Selected from hydrogen atoms, C 1-6 Alkyl and C 1-6 Halogenated alkyl; R B2 R B3 and R B4 Whether the same or different, and each independently selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl and cyano groups; L 2 For optional C 1-6 Alkyl-substituted propylene; ring C is thiazolyl or morpholino; R C Selected from halogens, C 1-6 Alkyl and C 1-6 Haloalkyl; p is 0 or 1; for R A Halogen or C 1-6 Alkyl; n is 0 or 1; L is

[0163] In some embodiments of this disclosure, the compound represented by the general formula (IIL) or a pharmaceutically acceptable salt thereof, wherein L 1 It is CH2 or cyclopropyl; XY is OCH2 or CH2OCH2; G 4 It is a carbon atom attached to a pyrrole ring, G 1 G 2 and G 3 They may be the same or different, and each is independently selected from N, CH and CR. 6 R 6 Selected from halogens, C 1-6 Alkyl and C 1-6 Alkoxy, wherein the C 1-6 Alkyl, C1-6 Each alkoxy group is independently selected from halogens, C... 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 One or more substituents in the haloalkoxy group are substituted; r is 0; R d Selected from hydrogen atoms, C 1-6 Alkyl, 3- to 6-membered cycloalkyl, 3- to 6-membered heterocyclic, 3- to 6-membered cycloalkyl C 1-6 Alkyl, 3 to 6-membered heterocyclic C 1-6 Alkyl, 3- to 6-membered cycloalkyl C 2-6 alkynyl, 3 to 6-membered heterocyclic C 2-6 alkynyl group; R B1 It is a hydrogen atom or a carbon atom. 1-6 Alkyl; R B2 R B3 and R B4 Whether the same or different, and each independently selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl and cyano groups; L 2 For optional C 1-6 Alkyl-substituted propylene group; ring C is thiazolyl; R C Selected from halogens, C 1-6 Alkyl and C 1-6 Haloalkyl; p is 0 or 1; for R A Halogen or C 1-6 Alkyl; n is 0 or 1; L is

[0164] In some embodiments of this disclosure, the compound represented by general formula (II) or a pharmaceutically acceptable salt thereof, wherein XY is OCH2 or CH2OCH2; G 1 G 2 G 3 and G 4 One of them is a carbon atom attached to a pyrrole ring, and the other three are the same or different, and each is independently CH, CR 6 Or N, R 6 Selected from halogens, C 1-6 Alkyl and C 1-6 Alkoxy, wherein the C 1-6 Alkyl, C 1-6 Each alkoxy group is independently selected from halogens, C... 1-6 Alkyl, C 1-6 Alkoxy, C1-6 Haloalkyl, C 1-6 One or more substituents in the haloalkoxy group are substituted; r is 0, 1 or 2; R D Selected from halogens, C 1-6 Alkyl, C 1-6 Haloalkyl; or two R atoms on the same atom D Together with the attached atom, it forms a cyclopropyl group; R d It is a hydrogen atom or a carbon atom. 1-6 Alkyl; R B1 It is a hydrogen atom or a carbon atom. 1-6 Alkyl; R B2 R B3 and R B4 Whether the same or different, and each independently selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl and cyano groups; L 2 For optional use by one or more C 1-6 Alkyl-substituted propylene; ring C is phenyl or 5 or 6-membered heteroaryl; R C Selected from halogens, C 1-6 Alkyl and C 1-6 Haloalkyl; p is 0, 1 or 2; for R A Halogen or C 1-6 Alkyl; n is 0 or 1; L is selected from

[0165] In some embodiments of this disclosure, the compound represented by general formula (III) or a pharmaceutically acceptable salt thereof, wherein m is 0 or 1; R 4aa They may be the same or different, and each is independently selected from halogens, C 1-6 Alkyl or C 1-6 Haloalkyl; m1 is 0, 1 or 2; G 1 For N; R 6A Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Alkoxy, wherein the C 1-6 Alkyl, C 1-6 Each alkoxy group is independently selected from halogens, C... 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 One or more substituents in the haloalkoxy group are substituted; R dIt is a hydrogen atom or a carbon atom. 1-6 Alkyl; R B1 It is a hydrogen atom or a carbon atom. 1-6 Alkyl; R B2 R B3 and R B4 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl and C 1-6 Halogenated alkyl; R C1 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; for L is

[0166] In some embodiments of this disclosure, the compound represented by the general formula (IIIL) or a pharmaceutically acceptable salt thereof, wherein L 1 It is CH2 or cyclopropyl; m is 0 or 1; R 4aa They may be the same or different, and each is independently selected from halogens, C 1-6 Alkyl or C 1-6 Haloalkyl; m1 is 0, 1 or 2; G 1 For N; R 6A Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Alkoxy, wherein the C 1-6 Alkyl, C 1-6 Each alkoxy group is independently selected from halogens, C... 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 One or more substituents in the haloalkoxy group are substituted; R d Selected from hydrogen atoms, C 1-6 Alkyl, 3- to 6-membered cycloalkyl, 3- to 6-membered heterocyclic, 3- to 6-membered cycloalkyl C 1-6 Alkyl, 3 to 6-membered heterocyclic C 1-6 Alkyl, 3- to 6-membered cycloalkyl C 2-6 alkynyl, 3 to 6-membered heterocyclic C 2-6 alkynyl group; R B1 Selected from hydrogen atoms, C 1-6 Alkyl and C 1-6 Halogenated alkyl; R B2 R B3 and R B4 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl and C 1-6 Halogenated alkyl; R C1 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C1-6 Halogenated alkyl groups; for L is

[0167] In some embodiments of this disclosure, the compound represented by the general formula (IIIL) or a pharmaceutically acceptable salt thereof, wherein L 1 It is CH2 or cyclopropyl; m is 0 or 1; R 4aa They may be the same or different, and each is independently selected from halogens, C 1-6 Alkyl or C 1-6 Haloalkyl; m1 is 0, 1 or 2; G 1 For N; R 6A Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Alkoxy, wherein the C 1-6 Alkyl, C 1-6 Each alkoxy group is independently selected from halogens, C... 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 One or more substituents in the haloalkoxy group are substituted; R d Selected from hydrogen atoms, C 1-6 Alkyl, 3- to 6-membered cycloalkyl, 3- to 6-membered heterocyclic, 3- to 6-membered cycloalkyl C 1-6 Alkyl, 3 to 6-membered heterocyclic C 1-6 Alkyl, 3- to 6-membered cycloalkyl C 2-6 alkynyl, 3 to 6-membered heterocyclic C 2-6 alkynyl group; R B1 It is a hydrogen atom or a carbon atom. 1-6 Alkyl; R B2 R B3 and R B4 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl and C 1-6 Halogenated alkyl; R C1 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; for L is

[0168] In some embodiments of this disclosure, the compound represented by the general formula (IIIL) or a pharmaceutically acceptable salt thereof, wherein L 1 It is CH2 or cyclopropyl; m is 0 or 1; R 4aa They may be the same or different, and each is independently selected from halogens, C 1-6 Alkyl or C 1-6Haloalkyl; m1 is 0, 1 or 2; G 1 For N; R 6A Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Alkoxy, wherein the C 1-6 Alkyl, C 1-6 Each alkoxy group is independently selected from halogens, C... 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 One or more substituents in the haloalkoxy group are substituted; R d Selected from hydrogen atoms, C 1-6 Alkyl, 3- to 6-membered cycloalkyl, 3- to 6-membered heterocyclic, 3- to 6-membered cycloalkyl C 1-6 Alkyl, 3 to 6-membered heterocyclic C 1-6 Alkyl, 3- to 6-membered cycloalkyl C 2-6 alkynyl, 3 to 6-membered heterocyclic C 2-6 alkynyl group; R B1 C 1-6 Halogenated alkyl; R B2 R B3 and R B4 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl and C 1-6 Halogenated alkyl; R C1 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; for L is

[0169] In some embodiments of this disclosure, the compound represented by the general formula (IIIL) or a pharmaceutically acceptable salt thereof, wherein L 1 Cyclopropyl; m = 1; R 4aa They may be the same or different, and each is independently selected from halogens, C 1-6 Alkyl or C 1-6 Haloalkyl; m1 is 0, 1 or 2; G 1 For N; R 6A Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Alkoxy, wherein the C 1-6 Alkyl, C 1-6 Each alkoxy group is independently selected from halogens, C... 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 One or more substituents in the haloalkoxy group are substituted; Rd Selected from hydrogen atoms, C 1-6 Alkyl, 3- to 6-membered cycloalkyl, 3- to 6-membered heterocyclic, 3- to 6-membered cycloalkyl C 1-6 Alkyl, 3 to 6-membered heterocyclic C 1-6 Alkyl, 3- to 6-membered cycloalkyl C 2-6 alkynyl, 3 to 6-membered heterocyclic C 2-6 alkynyl group; R B1 It is a hydrogen atom or a carbon atom. 1-6 Alkyl; R B2 R B3 and R B4 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl and C 1-6 Halogenated alkyl; R C1 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; for L is

[0170] In some embodiments of this disclosure, the compound represented by the general formula (IIIL) or a pharmaceutically acceptable salt thereof, wherein L 1 It is CH2 or cyclopropyl; m is 0 or 1; R 4aa They may be the same or different, and each is independently selected from halogens, C 1-6 Alkyl or C 1-6 Haloalkyl; m1 is 0, 1 or 2; G 1 For N; R 6A Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Alkoxy, wherein the C 1-6 Alkyl, C 1-6 Each alkoxy group is independently selected from halogens, C... 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 One or more substituents in the haloalkoxy group are substituted; R d Selected from hydrogen atoms, C 1-6 Alkyl, 3- to 6-membered cycloalkyl, 3- to 6-membered heterocyclic, 3- to 6-membered cycloalkyl C 1-6 Alkyl, 3 to 6-membered heterocyclic C 1-6 Alkyl, 3- to 6-membered cycloalkyl C 2-6 alkynyl, 3 to 6-membered heterocyclic C 2-6 alkynyl group; R B1 It is a hydrogen atom or a carbon atom. 1-6 Alkyl; R B2 R B3 and R B4They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl and C 1-6 Halogenated alkyl; R C1 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; for L is

[0171] In some embodiments of this disclosure, the compound represented by the general formula (IIIL) or a pharmaceutically acceptable salt thereof, wherein L 1 It is CH2 or cyclopropyl; m is 1; R 4aa They may be the same or different, and each is independently selected from halogens, C 1-6 Alkyl or C 1-6 Haloalkyl; m1 is 0, 1 or 2; G 1 For N; R 6A CH3OCH(CH3); R d Selected from hydrogen atom, methyl or cyclopropyl; R B1 It is a hydrogen atom or a carbon atom. 1-6 Alkyl; R B2 R B3 and R B4 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl and C 1-6 Halogenated alkyl; R C1 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; for L is

[0172] In some embodiments of this disclosure, the compound represented by general formula (III) or a pharmaceutically acceptable salt thereof, wherein m is 0; R 4aa They may be the same or different, and each is independently selected from halogens, C 1-6 Alkyl or C 1-6 Haloalkyl; m1 is 0, 1 or 2; G 1 For N; R 6A Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Alkoxy, wherein the C 1-6 Alkyl, C 1-6 Each alkoxy group is independently selected from halogens, C... 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 One or more substituents in the haloalkoxy group are substituted; Rd It is a hydrogen atom or a carbon atom. 1-6 Alkyl; R B1 It is a hydrogen atom or a carbon atom. 1-6 Alkyl; R B2 R B3 and R B4 They may be the same or different, and each is independently selected from hydrogen atoms or halogens; R C1 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; for L is

[0173] Table A lists typical compounds disclosed herein, including but not limited to:

[0174] This disclosure provides a compound of general formula (IA) or a salt thereof:

[0175] in,

[0176] G 1 G 2 G 3 G 4 X, Y, R D ,r,Rd R 2 L 2 Ring A, R A , n, L 1 R R , ring C, R C p, ring B, R B And q are as defined in general formula (I).

[0177] Furthermore, this disclosure provides a compound of general formula (IILA) or a salt thereof:

[0178] in:

[0179] L 1 G 1 G 2 G 3 G 4 X, Y, R D ,r,R d L 2 R A , n, ring C, R C p, R B1 R B2 R B3 R B4 The dashed line is as defined in the general formula (IIL).

[0180] Furthermore, this disclosure provides a compound of general formula (IIA) or a salt thereof:

[0181] in:

[0182] G 1 G 2 G 3 G 4 X, Y, R D ,r,R d L 2 R A , n, ring C, R C p, R B1 R B2 R B3 R B4 The dashed line is as defined in general formula (II).

[0183] This disclosure provides a compound of general formula (IIILA) or a salt thereof:

[0184] in:

[0185] L 1 G 1 R6A m, m1, R 4aa R d R A n, R C1 R B1 R B2 R B3 and R B4 As defined in general formula (IIIL).

[0186] This disclosure provides a compound of general formula (IVA) or a salt thereof:

[0187] in:

[0188] L 1 G 1 R 6A m, m1, R 4aa R A n, R C1 R B1 R B2 R B3 and R B4 As defined in general formula (IV).

[0189] This disclosure provides a compound of general formula (IIIA) or a salt thereof:

[0190] in:

[0191] G 1 R 6A m, m1, R 4aa R d R A n, R C1 R B1 R B2 R B3 and R B4 As defined in general formula (III).

[0192] This disclosure provides a compound of general formula (I) or a salt thereof:

[0193] in,

[0194] L is

[0195] R 11 R 12 , Ring W 1 G 1 G 2 G 3 G 4 X, Y, RD ,r,R d R 2 L 2 Ring A, R A , n, L 1 R R , ring C, R C p, ring B, R B And q as defined above.

[0196] This disclosure provides a compound of general formula (IIL) or a salt thereof:

[0197] in:

[0198] L is

[0199] R 11 R 12 , Ring W 1 L 1 G 1 G 2 G 3 G 4 X, Y, R D ,r,R d L 2 R A , n, ring C, R C p, R B1 R B2 R B3 R B4 The dashed line is as defined above.

[0200] This disclosure provides a compound of general formula (II) or a salt thereof:

[0201] in,

[0202] L is

[0203] R 11 R 12 , Ring W 1 G 1 G 2 G 3 G 4 X, Y, R D ,r,R d L 2 R A , n, ring C, R C p, R B1 R B2 R B3 RB4 The dashed line is as defined above.

[0204] This disclosure provides a compound of general formula (IIIL) or a salt thereof:

[0205] in:

[0206] L is

[0207] R 11 R 12 , Ring W 1 L 1 G 1 R 6A m, m1, R 4aa R d R A n, R C1 R B1 R B2 R B3 and R B4 As defined above.

[0208] This disclosure provides a compound of general formula (IV) or a salt thereof:

[0209] in:

[0210] L is

[0211] R 11 R 12 , Ring W 1 L 1 G 1 R 6A m, m1, R 4aa R A n, R C1 R B1 R B2 R B3 and R B4 As defined in general formula (IIIL).

[0212] This disclosure provides a compound of general formula (III) or a salt thereof:

[0213] in:

[0214] L is

[0215] R 11 R 12 , Ring W 1 G 1R 6A m, m1, R 4aa R d R A n, R C1 R B1 R B2 R B3 and R B4 As defined above.

[0216] In some embodiments of this disclosure, the pharmaceutically usable salt is a trifluoroacetate; in some embodiments, it is a hydrochloride; and in some embodiments, it is a bis(trifluoroacetate).

[0217] In some embodiments of this disclosure, the salt is a trifluoroacetate; in some embodiments, it is a hydrochloride; and in some embodiments, it is a bis(trifluoroacetate).

[0218] Table B lists typical intermediate compounds disclosed herein, including but not limited to:

[0219] Another aspect of this disclosure relates to a method for preparing a compound of general formula (I) or a pharmaceutically acceptable salt thereof, comprising:

[0220] The compound of general formula (IA) or its salt undergoes a condensation reaction with LC(O)OH or its salt to give the compound of general formula (I) or its pharmaceutically usable salt.

[0221] in:

[0222] G 1 G 2 G 3 G 4 X, Y, R D ,r,R d R 2 L 2 Ring A, R A , n, L 1 RR , ring C, R C p, ring B, R B And q are as defined in general formula (I).

[0223] Another aspect of this disclosure relates to a preparation for A method for processing compounds of general formulas (I), (II), (III), or (II) or pharmaceutically acceptable salts thereof, comprising:

[0224] Will for The compounds represented by general formulas (I), (II), and (II), or their pharmaceutically acceptable salts, were resolved to obtain... for The compounds of general formulas (I), (IIL), and (II) or their pharmaceutically usable salts; wherein all groups in general formula (I) are as defined in general formula (I), all groups in general formula (IIL) are as defined in general formula (IIL), and all groups in general formula (II) are as defined in general formula (II).

[0225] Another aspect of this disclosure relates to a preparation for A method for processing compounds of general formulas (I), (II), (III), or (II) or pharmaceutically acceptable salts thereof, comprising:

[0226] Will for The compounds represented by general formulas (I), (II), and (II), or their pharmaceutically acceptable salts, were resolved to obtain... for The compounds of general formulas (I), (IIL), and (II) or their pharmaceutically usable salts; wherein all groups in general formula (I) are as defined in general formula (I), all groups in general formula (IIL) are as defined in general formula (IIL), and all groups in general formula (II) are as defined in general formula (II).

[0227] Another aspect of this disclosure relates to a preparation for A method for processing compounds of general formulas (I), (II), (III), or (II) or pharmaceutically acceptable salts thereof, comprising:

[0228] Will for The compounds represented by general formulas (I), (II), and (II), or their pharmaceutically acceptable salts, were resolved to obtain... for The compounds of general formulas (I), (IIL), and (II) or their pharmaceutically usable salts; wherein all groups in general formula (I) are as defined in general formula (I), all groups in general formula (IIL) are as defined in general formula (IIL), and all groups in general formula (II) are as defined in general formula (II).

[0229] Another aspect of this disclosure relates to a preparation for A method for manufacturing compounds of general formulas (IIIL) and (III) or pharmaceutically acceptable salts thereof, comprising:

[0230] The compounds represented by general formulas (IIIL) and (III), or their pharmaceutically usable salts, are resolved to obtain for The compounds of general formula (IIIL) and (III) or their pharmaceutically usable salts; wherein all groups in general formula (IIIL) are as defined in general formula (IIIL), and all groups in general formula (III) are as defined in general formula (III).

[0231] Another aspect of this disclosure relates to a preparation for A method for manufacturing compounds of general formulas (IIIL) and (III) or pharmaceutically acceptable salts thereof, comprising:

[0232] Will for The compounds of general formulas (IIIL) and (III) or their pharmaceutically acceptable salts were resolved to obtain for The compounds of general formula (IIIL) and (III) or their pharmaceutically usable salts; wherein all groups in general formula (IIIL) are as defined in general formula (IIIL), and all groups in general formula (III) are as defined in general formula (III).

[0233] Another aspect of this disclosure relates to a preparation for A method for manufacturing compounds of general formulas (IIIL) and (III) or pharmaceutically acceptable salts thereof, comprising:

[0234] Will for The compounds of general formulas (IIIL) and (III) or their pharmaceutically acceptable salts were resolved to obtain for The compounds of general formula (IIIL) and (III) or their pharmaceutically usable salts; wherein all groups in general formula (IIIL) are as defined in general formula (IIIL), and all groups in general formula (III) are as defined in general formula (III).

[0235] Another aspect of this disclosure relates to a preparation for A method for processing a compound of general formula (IV) or a pharmaceutically acceptable salt thereof, comprising:

[0236] The compound represented by general formula (IV) or its pharmaceutically acceptable salt is resolved to obtain... for The compound represented by general formula (IV) or its pharmaceutically usable salt; wherein all groups in general formula (IV) are as defined in general formula (IV).

[0237] Another aspect of this disclosure relates to a preparation for A method for processing a compound of general formula (IV) or a pharmaceutically acceptable salt thereof, comprising:

[0238] Will for The compound represented by general formula (IV) or its pharmaceutically acceptable salt was resolved to obtain for The compound represented by general formula (IV) or its pharmaceutically usable salt; wherein all groups in general formula (IV) are as defined in general formula (IV).

[0239] Another aspect of this disclosure relates to a preparation for A method for processing a compound of general formula (IV) or a pharmaceutically acceptable salt thereof, comprising:

[0240] Will for The compound represented by general formula (IV) or its pharmaceutically acceptable salt was resolved to obtain for The compound represented by general formula (IV) or its pharmaceutically usable salt; wherein all groups in general formula (IV) are as defined in general formula (IV).

[0241] Another aspect of this disclosure relates to a method for preparing a compound of general formula (IIL) or a pharmaceutically acceptable salt thereof, comprising:

[0242] The compound represented by general formula (IILA) or its salt undergoes a condensation reaction with LC(O)OH or its salt to give the compound represented by general formula (IIL) or its pharmaceutically usable salt.

[0243] in:

[0244] L 1 L, G 1 G 2 G 3 G 4 X, Y, R D ,r,R d L 2 R A , n, ring C, R C p, R B1 R B2 R B3 R B4 The dashed line is as defined in the general formula (IIL).

[0245] Another aspect of this disclosure relates to a method for preparing a compound of general formula (II) or a pharmaceutically acceptable salt thereof, comprising:

[0246] The compound of general formula (IIA) or its salt undergoes a condensation reaction with LC(O)OH or its salt to give the compound of general formula (II) or its pharmaceutically usable salt.

[0247] in:

[0248] L, G 1 G 2 G 3 G 4 X, Y, R D ,r,R d L 2 R A , n, ring C, R C p, R B1 R B2 R B3 R B4 The dashed line is as defined in general formula (II).

[0249] Another aspect of this disclosure relates to a method for preparing a compound of general formula (IIIL) or a pharmaceutically acceptable salt thereof, comprising:

[0250] The compound represented by general formula (IIILA) or its salt undergoes a condensation reaction with LC(O)OH or its salt to give the compound represented by general formula (IIIL) or its pharmaceutically usable salt.

[0251] in:

[0252] L 1 L, G 1 R 6A m, m1, R 4aa R d R A n, R C1 R B1 R B2 R B3 and R B4 As defined in general formula (IIIL).

[0253] Another aspect of this disclosure relates to a method for preparing a compound of general formula (IV) or a pharmaceutically acceptable salt thereof, comprising:

[0254] The compound represented by general formula (IVA) or its salt reacts with LC(O)OH or its salt to give the compound represented by general formula (IV) or its pharmaceutically usable salt.

[0255] in:

[0256] L 1 L, G 1 R 6A m, m1, R 4aa R A n, R C1 R B1 R B2 R B3 and R B4 As defined in general formula (IV).

[0257] Another aspect of this disclosure relates to a method for preparing a compound of general formula (III) or a pharmaceutically acceptable salt thereof, comprising:

[0258] The compound of general formula (IIIA) or its salt undergoes a condensation reaction with LC(O)OH or its salt to give the compound of general formula (III) or its pharmaceutically usable salt.

[0259] in:

[0260] L, G 1 R 6A m, m1, R 4aa R d R A n, RC1 R B1 R B2 R B3 and R B4 As defined in general formula (III).

[0261] Another aspect of this disclosure relates to a method for preparing a compound of general formula (I) or a pharmaceutically acceptable salt thereof, comprising:

[0262] Let L be The compound or its salt represented by general formula (I) and It or its salt undergoes a condensation reaction to obtain L. The compound represented by general formula (I) or its pharmaceutically usable salt;

[0263] in:

[0264] R W4 For -OLi, -ONa, -OK, OH, halogens;

[0265] Ring W 2 R W3 w4, R 11 R 12 , Ring W 1 G 1 G 2 G 3 G 4 X, Y, R D ,r,R d R 2 L 2 Ring A, R A , n, L 1 R R , ring C, R C p, ring B, R B And q as defined above.

[0266] Another aspect of this disclosure relates to a method for preparing a compound of general formula (IIL) or a pharmaceutically acceptable salt thereof, comprising:

[0267] Let L be The compound or its salt represented by the general formula (IIL) and It or its salt undergoes a condensation reaction to obtain L. Compounds of the general formula (IIL) or their pharmaceutically usable salts;

[0268] in:

[0269] R W4 For -OLi, -ONa, -OK, OH, halogens;

[0270] Ring W2 R W3 w4, R 11 R 12 , Ring W 1 L 1 G 1 G 2 G 3 G 4 X, Y, R D ,r,R d L 2 R A , n, ring C, R C p, R B1 R B2 R B3 R B4 The dashed line is as defined above.

[0271] Another aspect of this disclosure relates to a method for preparing a compound of general formula (II) or a pharmaceutically acceptable salt thereof, comprising:

[0272] Let L be The compound of general formula (II) or its salt with It or its salt undergoes a condensation reaction to obtain L. The compound of general formula (II) or its pharmaceutically usable salt;

[0273] in:

[0274] R W4 For -OLi, -ONa, -OK, OH, halogens;

[0275] Ring W 2 R W3 w4, R 11 R 12 , Ring W 1 G 1 G 2 G 3 G 4 X, Y, R D ,r,R d L 2 R A , n, ring C, R C p, R B1 R B2 R B3 R B4 The dashed line is as defined above.

[0276] Another aspect of this disclosure relates to a method for preparing a compound of general formula (IIIL) or a pharmaceutically acceptable salt thereof, comprising:

[0277] Let L be Compounds of general formula (IIIL) or their salts with It or its salt undergoes a condensation reaction to obtain L. Compounds of general formula (IIIL) or their pharmaceutically usable salts;

[0278] in:

[0279] R W4 For -OLi, -ONa, -OK, OH, halogens;

[0280] Ring W 2 R W3 w4, R 11 R 12 , Ring W 1 L 1 G 1 R 6A m, m1, R 4aa R d R A n, R C1 R B1 R B2 R B3 and R B4 As defined above.

[0281] Another aspect of this disclosure relates to a method for preparing a compound of general formula (IV) or a pharmaceutically acceptable salt thereof, comprising:

[0282] Let L be The compound represented by general formula (IV) or its salt with It or its salt undergoes a condensation reaction to obtain L. Compounds of general formula (IV) or their pharmaceutically usable salts;

[0283] in:

[0284] R W4 For -OLi, -ONa, -OK, OH, halogens;

[0285] Ring W 2 R W3 w4, R 11 R 12 , Ring W 1 L 1 G 1 R 6A m, m1, R 4aa R A n, R C1 R B1 R B2 RB3 and R B4 As defined above.

[0286] Another aspect of this disclosure relates to a method for preparing a compound of general formula (III) or a pharmaceutically acceptable salt thereof, comprising:

[0287] Let L be The compound represented by general formula (III) or its salt with It or its salt undergoes a condensation reaction to obtain L. The compound of general formula (III) or its pharmaceutically usable salt;

[0288] in:

[0289] R W4 For -OLi, -ONa, -OK, OH, halogens;

[0290] Ring W 2 R W3 w4, R 11 R 12 , Ring W 1 G 1 R 6A m, m1, R 4aa R d R A n, R C1 R B1 R B2 R B3 and R B4 As defined above.

[0291] In some embodiments, the condensation reaction in the preparation methods of the general formulas (I), (II), (III), (IIL), (IIIL), and (IV) occurs under alkaline conditions in the presence of a condensing agent.

[0292] In some embodiments, the separation of the general formulas (I), (II), (III), (IIL), (IIIL), and (IV) is performed using high-performance liquid chromatography (HPLC) or thin-layer silica gel chromatography; in some embodiments, the separation is performed using HPLC.

[0293] In some embodiments, the reagents providing the alkaline conditions include organic and inorganic bases. The organic bases include, but are not limited to, triethylamine, N,N-diisopropylethylamine, n-butyllithium, diisopropylaminolithium, potassium acetate, sodium tert-butoxide, potassium tert-butoxide, tetrabutylammonium fluoride, tetrahydrofuran solution of tetrabutylammonium fluoride, or 1,8-diazabicycloundec-7-ene. The inorganic bases include, but are not limited to, sodium hydride, potassium phosphate, sodium carbonate, sodium acetate, potassium acetate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, cesium fluoride, and potassium hydroxide. In some embodiments, N,N-diisopropylethylamine is used.

[0294] In some embodiments, the condensing agent includes, but is not limited to, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, N,N'-dicyclohexylcarbodiimide, N,N'-diisopropylcarbodiimide, O-benzotriazole-N,N,N',N'-tetramethylurea tetrafluoroborate, 1-hydroxybenzotriazole, 1-hydroxy-7-azobenzotriazole, O-benzotriazole-N,N,N',N'-tetramethylurea hexafluorophosphate, and O-(7-azabenzotriazole-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate. Methylurea hexafluorophosphate (HATU), 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethylurea hexafluorophosphate, benzotriazole-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate, 1-cyano-2-ethoxy-2-oxoethyleneamino(oxy)dimethylamino-morpholino-carbomonium hexafluorophosphate (COMU) or benzotriazole-1-yl-oxytripyrrolylphosphine hexafluorophosphate; in some embodiments, the condensing agent is COMU; in some embodiments, the condensing agent is HATU.

[0295] The above synthesis can be carried out in any solvent, including but not limited to: ethylene glycol dimethyl ether, acetic acid, methanol, ethanol, acetonitrile, n-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1,4-dioxane, water, N,N-dimethylformamide, N,N-dimethylacetamide, and mixtures thereof.

[0296] Another aspect of this disclosure relates to a method for preparing compounds of general formula (III) or (IIIL) or pharmaceutically acceptable salts thereof (wherein) for The method includes:

[0297] The compound represented by general formula (III) or (IIIL) or its salt is resolved to obtain for Compounds of general formula (III) or (IIIL) or their pharmaceutically acceptable salts;

[0298] in:

[0299] L 1 L, G 1 R 6A m, m1, R 4aa R d R A n, R C1 R B1 R B2 R B3 and R B4 As defined in general formula (III) or (IIIL); in some embodiments, the separation is performed using high-performance liquid preparative chromatography.

[0300] Another aspect of this disclosure relates to a pharmaceutical composition comprising a compound of the above-described formulas (I), (II), (III), (IIL), (IIIL), (IV) or Table A, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.

[0301] This disclosure further relates to the use of compounds of general formula (I), general formula (II), general formula (III), general formula (IIL), general formula (IIIL), (IV) or Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising them, in the preparation of a medicament for inhibiting RAS mutant proteins.

[0302] This disclosure further relates to the use of compounds of general formula (I), general formula (II), general formula (III), general formula (IIL), general formula (IIIL), (IV) or Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising them, in the preparation of medicaments for the treatment and / or prevention of diseases or conditions mediated or dependent on RAS mutant proteins.

[0303] This disclosure further relates to the use of compounds of general formula (I), general formula (II), general formula (III), general formula (IIL), general formula (IIIL), (IV) or Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising them, in the preparation of medicaments for the treatment and / or prevention of tumors.

[0304] This disclosure also relates to a method for inhibiting a mutant RAS protein in a subject, comprising administering to the desired subject a compound of the above formula (I), formula (II), formula (III), formula (IIL), formula (IIIL), (IV) or Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the above.

[0305] This disclosure also relates to a method of treating and / or preventing diseases or conditions mediated or dependent on RAS mutant proteins, comprising administering to a desired patient a compound of the above general formula (I), general formula (II), general formula (III), general formula (IIL), general formula (IIIL), (IV) or Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the above.

[0306] This disclosure also relates to a method of treating and / or preventing tumors, comprising administering to a desired patient a compound of the above general formula (I), general formula (II), general formula (III), general formula (IIL), general formula (IIIL), (IV) or Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the above.

[0307] This disclosure further relates to a compound of the above general formula (I), general formula (II), general formula (III), general formula (IIL), general formula (IIIL), (IV) or Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the above, which is used as a medicine.

[0308] This disclosure further relates to a compound of the above general formula (I), general formula (II), general formula (III), general formula (IIL), general formula (IIIL), (IV) or Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the above, which is used as a medicament for treating and / or preventing diseases or conditions mediated or dependent on the RAS mutant protein.

[0309] This disclosure further relates to compounds of the above general formulas (I), (II), (III), (IIL), (IIIL), (IV) or Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising thereof, for use in inhibiting RAS mutant proteins in a subject.

[0310] This disclosure further relates to compounds of the above general formulas (I), (II), (III), (IIL), (IIIL), (IV) or Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising them, for the treatment and / or prevention of diseases or conditions mediated or dependent on the RAS mutant protein.

[0311] This disclosure further relates to compounds of the above general formulas (I), (II), (III), (IIL), (IIIL), (IV) or Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising them, for the treatment and / or prevention of tumors.

[0312] In some embodiments, the diseases or conditions mediated or dependent on the RAS mutant protein described in this disclosure are tumors; in some embodiments, the diseases or conditions mediated or dependent on the RAS mutant protein described in this disclosure are selected from thyroid cancer, head and neck cancer, esophageal cancer, gastric cancer, lung cancer, liver cancer, kidney cancer, pancreatic cancer, gallbladder cancer, brain cancer, skin cancer, testicular cancer, bile duct cancer, colorectal cancer, urothelial carcinoma, bladder cancer, breast cancer, ovarian cancer, uterine cancer, endometrial cancer, cervical cancer, prostate cancer, leukemia, lymphoma, myeloma, appendix cancer, melanoma, sarcoma, and glioblastoma; in some embodiments, the diseases or conditions mediated or dependent on the RAS mutant protein described in this disclosure are selected from gastric cancer, pancreatic cancer, colorectal cancer, and non-small cell lung cancer.

[0313] In some embodiments, the tumors described in this disclosure are selected from thyroid cancer, head and neck cancer, esophageal cancer, gastric cancer, lung cancer, liver cancer, kidney cancer, pancreatic cancer, gallbladder cancer, brain cancer, skin cancer, testicular cancer, bile duct cancer, colorectal cancer, urothelial carcinoma, bladder cancer, breast cancer, ovarian cancer, uterine cancer, endometrial cancer, cervical cancer, prostate cancer, leukemia, lymphoma, myeloma, appendix cancer, melanoma, sarcoma, and glioblastoma; in some embodiments, the tumors described in this disclosure are selected from gastric cancer, pancreatic cancer, colorectal cancer, and non-small cell lung cancer.

[0314] In some implementations, the tumor described in this disclosure is a solid tumor.

[0315] In some embodiments, the tumors described in this disclosure are hematologic malignancies.

[0316] In some embodiments, the sarcomas described in this disclosure are angiosarcomas, fibrosarcomas, rhabdomyosarcomas, liposarcomas, chondrosarcomas, Ewing's sarcoma, and Kaposi's sarcoma.

[0317] In some embodiments, the colorectal cancer described in this disclosure is colon cancer or rectal cancer.

[0318] In some embodiments, the lymphomas described in this disclosure are diffuse large B-cell lymphomas, Hodgkin's disease, and non-Hodgkin's lymphomas.

[0319] In some embodiments, the lung cancer described in this disclosure is lung adenocarcinoma; in some embodiments, the lung cancer is squamous cell lung cancer or small cell lung cancer; and in some embodiments, it is non-small cell lung cancer (NSCLC).

[0320] In some implementations, the leukemias described in this disclosure are chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), and chronic myeloid leukemia.

[0321] In some embodiments, the myeloma described in this disclosure is multiple myeloma.

[0322] In some embodiments, the head and neck cancer described in this disclosure is head and neck squamous cell carcinoma (HNSCC).

[0323] In some implementations, the esophageal cancer described in this disclosure is gastric esophageal cancer.

[0324] In some implementations, the liver cancer described in this disclosure is hepatocellular carcinoma, hepatoblastoma, or hepatocellular adenoma.

[0325] In some embodiments, the RAS protein described in this disclosure is selected from K-Ras G12C, K-Ras G12D, K-Ras G12V, K-Ras G12A, K-Ras G12S, K-Ras G12R, K-Ras G13C, K-Ras G13D, K-Ras Q61H, K-Ras Q61R, K-Ras Q61K, or K-Ras Q61L; in some embodiments, the Ras protein is selected from N-Ras G12D, N-Ras G13D, N-Ras Q61R, N-Ras Q61K, N-Ras Q61L, N-Ras Q61H, or N-Ras Q61P; in some embodiments, the Ras protein is selected from H-Ras G12D, H-Ras G12V, H-Ras G13R, H-Ras Q61R, H-Ras Q61L; In some embodiments, the Ras protein is selected from K-Ras G12D, N-Ras G12D, and H-Ras G12D.

[0326] The active compound can be formulated in a form suitable for administration via any appropriate route, in some embodiments in the form of a unit dose or in a form that a patient can self-administer as a single dose. The unit dose of the disclosed compound or composition can be expressed as a tablet, capsule, sachet, bottled liquid, powder, granule, lozenge, suppository, regenerated powder, or liquid formulation.

[0327] As a general guideline, a suitable unit dose can be 0.1–1000 mg.

[0328] In addition to the active compound, the pharmaceutical compositions disclosed herein may contain one or more excipients selected from the following: fillers (diluents), binders, wetting agents, disintegrants, or excipients. Depending on the method of administration, the composition may contain 0.1 to 99% by weight of the active compound.

[0329] In addition to the active compound, the pharmaceutical compositions disclosed herein may contain one or more excipients selected from the following: fillers (diluents), binders, wetting agents, disintegrants, or excipients. Depending on the method of administration, the composition may contain 0.1 to 99% by weight of the active compound.

[0330] In some embodiments, the unit dose of the pharmaceutical composition is 0.001 mg to 1000 mg.

[0331] In some embodiments, the pharmaceutical composition contains 0.01-99.99% of the aforementioned compound or its pharmaceutically acceptable salt or isotopic substitution, based on the total weight of the composition. In some embodiments, the pharmaceutical composition contains 0.1-99.9% of the aforementioned compound or its pharmaceutically acceptable salt or isotopic substitution. In some embodiments, the pharmaceutical composition contains 0.5%-99.5% of the aforementioned compound or its pharmaceutically acceptable salt or isotopic substitution. In some embodiments, the pharmaceutical composition contains 1%-99% of the aforementioned compound or its pharmaceutically acceptable salt or isotopic substitution. In some embodiments, the pharmaceutical composition contains 2%-98% of the aforementioned compound or its pharmaceutically acceptable salt or isotopic substitution.

[0332] In some embodiments, the pharmaceutical composition contains 0.01% to 99.99% pharmaceutically acceptable excipients based on the total weight of the composition. In some embodiments, the pharmaceutical composition contains 0.1% to 99.9% pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical composition contains 0.5% to 99.5% pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical composition contains 1% to 99% pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical composition contains 2% to 98% pharmaceutically acceptable excipients.

[0333] The pharmaceutically acceptable salts of the compounds described in this disclosure may be selected from inorganic or organic salts.

[0334] Pharmaceutical compositions containing active ingredients may be in forms suitable for oral administration, such as tablets, sugar lozenges, tablets, aqueous or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Oral compositions may be prepared according to any method known in the art for preparing pharmaceutical compositions, and such compositions may contain one or more ingredients selected from sweeteners, flavoring agents, coloring agents, and preservatives to provide an appealing and palatable pharmaceutical formulation.

[0335] Tablets contain an active ingredient and non-toxic, pharmaceutically acceptable excipients suitable for tablet preparation, used for mixing. These excipients may be inert excipients, granulating agents, disintegrants, binders, and lubricants. These tablets may be uncoated or coated using known techniques that mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract, thus providing sustained release over a longer period.

[0336] Oral formulations can also be provided using soft gelatin capsules in which the active ingredient is mixed with an inert solid diluent or in which the active ingredient is mixed with a water-soluble carrier or an oil solvent.

[0337] Aqueous suspensions contain active substances and excipients suitable for preparing aqueous suspensions for mixing. These excipients are suspending agents, dispersing agents, or wetting agents. Aqueous suspensions may also contain one or more preservatives, one or more coloring agents, one or more flavoring agents, and one or more sweeteners.

[0338] Oil suspensions are formulated by suspending the active ingredient in vegetable or mineral oil. Oil suspensions may contain thickeners. Sweeteners and flavoring agents mentioned above may be added to provide palatable formulations. These compositions may be preserved by adding antioxidants.

[0339] The pharmaceutical compositions disclosed herein may also be in the form of an oil-in-water emulsion. The oil phase may be vegetable oil, mineral oil, or a mixture thereof. Suitable emulsifiers may be naturally occurring phospholipids, and the emulsion may also contain sweeteners, flavoring agents, preservatives, and antioxidants. Such formulations may also contain modifiers, preservatives, colorants, and antioxidants.

[0340] The pharmaceutical compositions disclosed herein may be in the form of sterile injectable aqueous solutions. Acceptable solvents or media that can be used include water, Ringer's solution, and isotonic sodium chloride solution. The sterile injectable formulation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in the oil phase, which can be injected into the patient's bloodstream via local large-volume injection. Alternatively, the solution and microemulsion are preferably administered in a manner that maintains a constant circulating concentration of the compounds disclosed herein. To maintain such a constant concentration, a continuous intravenous delivery device may be used. An example of such a device is the Deltec CADD-PLUS™ 5400 intravenous infusion pump.

[0341] The pharmaceutical compositions disclosed herein may be in the form of sterile injectable aqueous or oil suspensions for intramuscular and subcutaneous administration. These suspensions may be formulated using suitable dispersants or wetting agents and suspending agents according to known techniques. The sterile injectable formulations may also be sterile injectable solutions or suspensions prepared in parenteral acceptable non-toxic diluents or solvents. Furthermore, sterile fixative oils can be conveniently used as solvents or suspension media. Any blended fixative oil may be used for this purpose. Additionally, fatty acids may also be used to prepare injectable formulations.

[0342] The disclosed compounds can be administered in suppository form for rectal administration. These pharmaceutical compositions can be prepared by mixing the drug with a suitable, non-irritating excipient that is solid at normal temperatures but liquid in the rectum, and thus dissolves in the rectum to release the drug.

[0343] As is well known to those skilled in the art, the dosage of a drug depends on a variety of factors, including but not limited to: the activity of the specific compound used, the patient's age, the patient's weight, the patient's health status, the patient's behavior, the patient's diet, the timing of administration, the route of administration, the rate of excretion, the combination of drugs, the severity of the disease, etc.; in addition, the optimal treatment mode, such as the treatment pattern, the daily dosage of the compound, or the type of medicinal salt can be validated based on conventional treatment protocols.

[0344] Terminology Explanation

[0345] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0346] The term "alkyl" refers to a saturated, straight-chain or branched aliphatic hydrocarbon group having 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) carbon atoms (i.e., C2). 1-20 Alkyl group). In some embodiments, the alkyl group is an alkyl group having 1 to 12 carbon atoms (i.e., C12). 1-12 Alkyl groups, in some embodiments, having 1 to 6 carbon atoms (i.e., C14-C6 ... 1-6Alkyl groups). Non-limiting examples include: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2 3-Dimethylpentyl, 2,4-Dimethylpentyl, 2,2-Dimethylpentyl, 3,3-Dimethylpentyl, 2-Ethylpentyl, 3-Ethylpentyl, n-Octyl, 2,3-Dimethylhexyl, 2,4-Dimethylhexyl, 2,5-Dimethylhexyl, 2,2-Dimethylhexyl, 3,3-Dimethylhexyl, 4,4-Dimethylhexyl, 2-Ethylhexyl, 3-Ethylhexyl, 4-Ethylhexyl, 2-Methyl-2-Ethylpentyl, 2-Methyl-3-Ethylpentyl, n-Nonyl, 2-Methyl-2-Ethylhexyl, 2-Methyl-3-Ethylhexyl, 2,2-Diethylpentyl, n-Decyl, 3,3-Diethylhexyl, 2,2-Diethylhexyl, and their various branched isomers, etc. Alkyl groups can be substituted or unsubstituted. When substituted, they can be substituted at any usable connection point. The substituents are selected from one or more of the following: D atom, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0347] The term "alkylene" refers to a divalent alkyl group, wherein the alkyl group, as defined above, has 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) carbon atoms (i.e., C2). 1-20 Alkylene). In some embodiments, the alkylene is an alkylene having 1 to 10 carbon atoms (i.e., C10). 1-10 Alkylenes), in some embodiments, alkylenes having 1 to 8 carbon atoms (i.e., C1646-C ... 1-8 Alkylenes), in some embodiments, alkylenes having 2 to 7 carbon atoms (i.e., C646-C ... 2-7 Alkylenes or alkylenes having 1, 2 or 3 carbon atoms (i.e., C14) 1-6Alkylenes. Non-limiting examples include: -CH2-, -CH(CH3)-, -C(CH3)2-, -CH2CH2-, -CH(CH2CH3)-, -CH2CH(CH3)-, -CH2C(CH3)2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, etc. Alkylenes can be substituted or unsubstituted, and when substituted, they can be substituted at any usable linking point. Substituents are selected from one or more of deuterium, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0348] The term "heteroalkyl" refers to an alkyl group in which one or more (e.g., 1, 2, 3, 4, 5, or 6) carbon atoms are replaced by heteroatoms selected from N, O, S, S(O), and S(O)2, and the nitrogen atom may optionally be quaternized, wherein the alkyl group is as defined above; in some embodiments, the heteroalkyl group is C 1-6 One, two, or three carbon atoms in the alkyl group are replaced by heteroatoms selected from N, O, S, S(O), and S(O)2; in some embodiments, the heteroalkyl group is a 2- to 6-membered heteroalkyl group (i.e., a total number of 2 to 6 atoms). The heteroalkyl group can be substituted or unsubstituted, and when substituted, it can be substituted at any usable linker, with the substituent selected from one or more of deuterium, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0349] The term "alkenyl" refers to an alkyl group in which the molecule contains at least one carbon-carbon double bond, wherein the alkyl group is defined as described above and has 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12) carbon atoms (i.e., C atoms). 2-12 Alkenyl). In some embodiments, the alkenyl group is an alkenyl group having 2 to 6 carbon atoms (i.e., C10). 2-6 Alkenyl). Non-limiting examples include vinyl, propenyl, isopropenyl, butenyl, etc. Alkenyl groups can be substituted or unsubstituted, and when substituted, they can be substituted at any usable linker. Substituents are selected from one or more of deuterium, alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0350] The term "alkynyl" refers to an alkyl group in a molecule that contains at least one carbon-carbon triple bond, wherein the alkyl group is defined as described above and has 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12) carbon atoms (i.e., C64, C74, C84, C9 ... 2-12(Alynyl group). In some embodiments, the alkynyl group is an alkynyl group having 2 to 6 carbon atoms (i.e., C12). 2-6 (Alynyl). Non-limiting examples include: ethynyl, propynyl, butynyl, pentyynyl, hexynyl, etc. The alkynyl group can be substituted or unsubstituted, and when substituted, it can be substituted at any usable linker. The substituent is selected from one or more of deuterium, alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0351] The term "alkoxy" refers to -O-(alkyl), where alkyl is defined as described above. Non-limiting examples include methoxy, ethoxy, propoxy, and butoxy, etc. Alkoxy groups can be substituted or unsubstituted, and when substituted, they can be substituted at any usable linker. Substituents are selected from one or more of deuterium, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0352] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic carbocyclic (i.e., monocyclic cycloalkyl) or polycyclic system (i.e., polycyclic cycloalkyl) having 3 to 20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., 3 to 20 membered cycloalkyl). In some embodiments, the cycloalkyl is a cycloalkyl having 3 to 12 ring atoms (i.e., 3 to 12 membered cycloalkyl) or a cycloalkyl having 4 to 11 ring atoms (i.e., 4 to 11 membered cycloalkyl), in some embodiments a cycloalkyl having 3 to 8 ring atoms (i.e., 3 to 8 membered cycloalkyl), and in some embodiments a cycloalkyl having 3 to 6 ring atoms (i.e., 3 to 6 membered cycloalkyl).

[0353] Non-limiting examples of the monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclohepttrienyl, and cyclooctyl.

[0354] The polycyclic alkyl groups include: spirocyclic alkyl groups, fused cyclic alkyl groups, and bridged cyclic alkyl groups.

[0355] The term "spirocycloalkyl" refers to a polycyclic system in which rings share a single carbon atom (called a spiro atom), and the ring may contain one or more double bonds, or one or more heteroatoms selected from nitrogen, oxygen, and sulfur (the nitrogen may optionally be oxidized to form nitrogen oxides; the sulfur may optionally be oxidized to form sulfoxides or sulfones, but excluding -OO-, -OS-, or -SS-), provided that it contains at least one full carbon ring with a bonding point on that full carbon ring, having 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., 5 to 20-membered spirocycloalkyl). In some embodiments, the spirocycloalkyl is a spirocycloalkyl having 6 to 14 ring atoms (i.e., 6 to 14-membered spirocycloalkyl), and in some embodiments, a spirocycloalkyl having 7 to 10 ring atoms (i.e., 7 to 10-membered spirocycloalkyl). The spirocycloalkyl group includes monospirocycloalkyl and polyspirocycloalkyl (such as bispirocycloalkyl, etc.). In some embodiments, it is a monospirocycloalkyl or bispirocycloalkyl group. In some embodiments, it is a 3-membered / 4-membered, 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 3-membered, 5-membered / 4-membered, 5-membered / 5-membered, 5-membered / 6-membered, 5-membered / 7-membered, 6-membered / 3-membered, 6-membered / 4-membered, 6-membered / 5-membered, 6-membered / 6-membered, 6-membered / 7-membered, 7-membered / 5-membered, or 7-membered / 6-membered monospirocycloalkyl group. Non-limiting examples include:

[0356] Its connection point can be anywhere;

[0357] wait.

[0358] The term "fused cycloalkyl" refers to a polycyclic system in which two adjacent carbon atoms are shared between rings. This system is a monocyclic cycloalkyl group fused with one or more monocyclic cycloalkyl groups, or a monocyclic cycloalkyl group fused with one or more heterocyclic, aryl, or heteroaryl groups, wherein the bonding point is on the monocyclic cycloalkyl group, which may contain one or more double bonds and has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., 5 to 20-membered fused cycloalkyl). In some embodiments, the fused cycloalkyl group is a fused cycloalkyl group having 6 to 14 ring atoms (i.e., 6 to 14-membered fused cycloalkyl), and in some embodiments, a fused cycloalkyl group having 7 to 10 ring atoms (i.e., 7 to 10-membered fused cycloalkyl). The fused cyclic alkyl group includes bicyclic fused cyclic alkyl groups and polycyclic fused cyclic alkyl groups (such as tricyclic fused cyclic alkyl groups, tetracyclic fused cyclic alkyl groups, etc.). In some embodiments, it is a bicyclic fused cyclic alkyl group or a tricyclic fused cyclic alkyl group. In some embodiments, it is a ternary / quadrivalent, ternary / quinary, ternary / six-membered, quadrivalent / quadrivalent, quadrivalent / five-membered, quadrivalent / six-membered, quadrivalent / quadrivalent, quadrivalent / six-membered, 5-member / tertiary, 5-member / quadrivalent, 5-member / five-membered, 5-member / six-membered, 5-member / seven-membered, 6-member / tertiary, 6-member / quadrivalent, 6-member / four-membered, 6-member / five-membered, 6-member / six-membered, 6-member / seven-membered, 7-member / five-membered, or 7-member / six-member bicyclic fused cyclic alkyl group. Non-limiting examples include:

[0359] Its connection point can be anywhere;

[0360] wait.

[0361] The term "bridged cycloalkyl" refers to a fully carbon polycyclic system in which two non-directly connected carbon atoms are shared between rings, and the ring may contain one or more double bonds and have 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) carbon atoms (i.e., 5 to 20-membered bridged cycloalkyl). In some embodiments, the bridged cycloalkyl is a bridged cycloalkyl having 6 to 14 carbon atoms (i.e., 6 to 14-membered bridged cycloalkyl), and in some embodiments, a bridged cycloalkyl having 7 to 10 carbon atoms (i.e., 7 to 10-membered bridged cycloalkyl). The bridged cycloalkyl includes bicyclic bridged cycloalkyl and polycyclic bridged cycloalkyl (e.g., tricyclic bridged cycloalkyl, tetracyclic bridged cycloalkyl, etc.), and in some embodiments, is a bicyclic bridged cycloalkyl or a tricyclic bridged cycloalkyl. Non-limiting examples include: Its connection point can be anywhere.

[0362] The cycloalkyl group can be substituted or unsubstituted. When substituted, it can be substituted at any usable connection point. The substituent is selected from one or more of the following: deuterium, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, alkylthio, haloalkylthio, cycloalkylthio, heterocyclic thio, heterocyclic oxy, hydroxy, hydroxyalkyl, oxo, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0363] The term "heterocyclic group" refers to a saturated or partially unsaturated monocyclic heterocycle (i.e., monocyclic heterocyclic group) or polycyclic heterocyclic system (i.e., polycyclic heterocyclic group) containing at least one (e.g., 1, 2, 3 or 4) heteroatoms selected from nitrogen, oxygen and sulfur (the nitrogen may optionally be oxidized, i.e., to form nitrogen oxides; the sulfur may optionally be oxidized, i.e., to form sulfoxides or sulfones, but excluding -OO-, -OS- or -SS-), and having 3 to 20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e., 3 to 20 membered heterocyclic groups). In some embodiments, the heterocyclic group is a heterocyclic group having 3 to 12 ring atoms (i.e., a 3 to 12-membered heterocyclic group) or a heterocyclic group having 4 to 11 ring atoms (i.e., a 4 to 11-membered heterocyclic group); in some embodiments, a heterocyclic group having 3 to 8 ring atoms (i.e., a 3 to 8-membered heterocyclic group); in some embodiments, a heterocyclic group having 3 to 6 ring atoms (i.e., a 3 to 6-membered heterocyclic group); in some embodiments, a heterocyclic group having 5 or 6 ring atoms (i.e., a 5 or 6-membered heterocyclic group).

[0364] Non-limiting examples of the monocyclic heterocyclic group include: pyrrolidinyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, and homopiperazinyl, etc.

[0365] The polycyclic heterocyclic groups include spirocyclic heterocyclic groups, fused heterocyclic groups, and bridged heterocyclic groups.

[0366] The term "spiroheterocyclic group" refers to a polycyclic heterocyclic system in which rings share a single atom (called a spiro atom), which may contain one or more double bonds and at least one (e.g., 1, 2, 3, or 4) heteroatoms selected from nitrogen, oxygen, and sulfur (the nitrogen may optionally be oxidized to form nitrogen oxides; the sulfur may optionally be oxidized to form sulfoxides or sulfones, but excluding -OO-, -OS-, or -SS-), provided that at least one monocyclic heterocyclic group is present and the bonding point is on the monocyclic heterocyclic group, which has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., 5 to 20-membered spiroheterocyclic groups). In some embodiments, the spiroheterocyclic group is a spiroheterocyclic group having 6 to 14 ring atoms (i.e., a 6 to 14-membered spiroheterocyclic group), and in some embodiments, a spiroheterocyclic group having 7 to 11 ring atoms (i.e., a 7 to 11-membered spiroheterocyclic group). The spiroheterocyclic group includes monospirocyclic and polyspirocyclic groups (such as bispirocyclic groups). In some embodiments, it is a monospirocyclic or bispirocyclic group. In some embodiments, it is a 3-membered / 4-membered, 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 3-membered, 5-membered / 4-membered, 5-membered / 5-membered, 5-membered / 6-membered, 5-membered / 7-membered, 6-membered / 3-membered, 6-membered / 4-membered, 6-membered / 5-membered, 6-membered / 6-membered, 6-membered / 7-membered, 7-membered / 5-membered, or 7-membered / 6-membered monospirocyclic group. Non-limiting examples include: wait.

[0367] The term "fused heterocyclic group" refers to a polycyclic heterocyclic system in which two adjacent atoms are shared between rings. The ring may contain one or more double bonds and at least one (e.g., 1, 2, 3, or 4) heteroatoms selected from nitrogen, oxygen, and sulfur (the nitrogen may optionally be oxidized to form nitrogen oxides; the sulfur may optionally be oxidized to form sulfoxides or sulfones, but excluding -OO-, -OS-, or -SS-). It is a monocyclic heterocyclic group fused with one or more monocyclic heterocyclic groups, or a monocyclic heterocyclic group fused with one or more cycloalkyl, aryl, or heteroaryl groups, wherein the bonding point is on the monocyclic heterocyclic group and has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., 5 to 20 membered fused heterocyclic groups). In some embodiments, the fused heterocyclic group is a fused heterocyclic group having 6 to 14 ring atoms (i.e., a 6 to 14-membered fused heterocyclic group), and in some embodiments, a fused heterocyclic group having 7 to 11 ring atoms (i.e., a 7 to 11-membered fused heterocyclic group). The fused heterocyclic group includes bicyclic and polycyclic fused heterocyclic groups (such as tricyclic fused heterocyclic groups, tetracyclic fused heterocyclic groups, etc.). In some embodiments, it is a bicyclic or tricyclic fused heterocyclic group. In some embodiments, it is a 3-membered / 4-membered, 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 3-membered, 5-membered / 4-membered, 5-membered / 5-membered, 5-membered / 6-membered, 5-membered / 7-membered, 6-membered / 3-membered, 6-membered / 4-membered, 6-membered / 5-membered, 6-membered / 6-membered, 6-membered / 7-membered, 7-membered / 5-membered, or 7-membered / 6-membered bicyclic fused heterocyclic group. Non-limiting examples include: wait.

[0368] The term "bridged heterocyclic group" refers to a polycyclic heterocyclic system in which two non-directly bonded atoms are shared between the rings. The rings may contain one or more double bonds and at least one (e.g., 1, 2, 3, or 4) heteroatoms selected from nitrogen, oxygen, and sulfur (the nitrogen may optionally be oxidized to form nitrogen oxides; the sulfur may optionally be oxidized to form sulfoxides or sulfones, but excluding -OO-, -OS-, or -SS-), having 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., 5 to 20-membered bridged heterocyclic groups). In some embodiments, the bridged heterocyclic group is a bridged heterocyclic group having 6 to 14 ring atoms (i.e., 6 to 14-membered bridged heterocyclic groups), and in some embodiments, a bridged heterocyclic group having 7 to 10 ring atoms (i.e., 7 to 10-membered bridged heterocyclic groups). Based on the number of constituent rings, heterocyclic groups can be classified into bicyclic bridged heterocyclic groups and multicyclic bridged heterocyclic groups (such as tricyclic bridged heterocyclic groups, tetracyclic bridged heterocyclic groups, etc.). In some embodiments, they are bicyclic bridged heterocyclic groups or tricyclic bridged heterocyclic groups. Non-limiting examples include:

[0369] wait.

[0370] The heterocyclic group can be substituted or unsubstituted. When substituted, it can be substituted at any usable connection point. The substituent is selected from one or more of the following: deuterium, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, alkylthio, haloalkylthio, cycloalkylthio, heterocyclic thio, hydroxy, hydroxyalkyl, oxo, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0371] The term "aryl" refers to a monocyclic all-carbon aromatic ring (i.e., a monocyclic aryl) or a polycyclic aromatic ring system (i.e., a polycyclic aryl) having a conjugated π-electron system, having 6 to 14 (e.g., 6, 7, 8, 9, 10, 11, 12, 13, or 14) ring atoms (i.e., a 6 to 14-membered aryl). In some embodiments, the aryl is an aryl having 6 to 10 ring atoms (i.e., a 6 to 10-membered aryl). The monocyclic aryl is, for example, phenyl. Non-limiting examples of the polycyclic aryl include naphthyl, anthraceneyl, phenanthrene, etc. The polycyclic aryl further includes fusion of the phenyl with one or more heterocyclic or cycloalkyl groups, or fusion of the naphthyl with one or more heterocyclic or cycloalkyl groups, wherein the bonding point is on the phenyl or naphthyl group, and in this case, the number of ring atoms continues to represent the number of ring atoms in the polycyclic aromatic ring system, non-limiting examples including:

[0372] wait.

[0373] The aryl group can be substituted or unsubstituted. When substituted, it can be substituted at any usable connection point. The substituent is selected from one or more of the following: deuterium, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxyl, alkylthio, haloalkylthio, cycloalkylthio, heterocyclic thio, hydroxyalkyl, oxo, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0374] The term "heteroaryl" refers to a monocyclic heteroaryl ring (i.e., monocyclic heteroaryl) or a polycyclic heteroaryl ring system (i.e., polycyclic heteroaryl) having a conjugated π-electron system, containing at least one (e.g., 1, 2, 3, or 4) heteroatoms selected from nitrogen, oxygen, and sulfur (the nitrogen may optionally be oxidized, i.e., to form nitrogen oxides; the sulfur may optionally be oxidized, i.e., to form sulfoxides or sulfones, but excluding -OO-, -OS-, or -SS-), having 5 to 14 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14) ring atoms (i.e., 5 to 14-membered heteroaryl). In some embodiments, the heteroaryl is a heteroaryl having 5 to 10 ring atoms (i.e., 5 to 10-membered heteroaryl), and in some embodiments, a heteroaryl having 5 or 6 ring atoms (i.e., 5 or 6-membered heteroaryl).

[0375] Non-limiting examples of the aforementioned monocyclic heteroaryl groups include: furanyl, thiopheneyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furazonyl, pyrroleyl, N-alkylpyrroleyl, pyridyl, pyrimidinyl, pyridoneyl, N-alkylpyridone (e.g.) (etc.), pyrazinyl, pyridazinyl, etc.

[0376] Non-limiting examples of the polycyclic heteroaryl groups include: indolyl, indazole, quinolinyl, isoquinolinyl, quinoxalinyl, phthalazinyl, benzimidazolyl, benzothiophene, quinazolinyl, benzothiazolyl, carbazole, etc. The polycyclic heteroaryl groups also include monocyclic heteroaryl groups fused with one or more aryl groups, wherein the connecting point is on the aromatic ring, and in this case, the number of ring atoms continues to represent the number of ring atoms in the polycyclic heteroaryl ring system. The polycyclic heteroaryl groups also include monocyclic heteroaryl groups fused with one or more cycloalkyl or heterocyclic groups, wherein the connecting point is on the monocyclic heteroaryl ring, and in this case, the number of ring atoms continues to represent the number of ring atoms in the polycyclic heteroaryl ring system. Non-limiting examples include: wait.

[0377] The heteroaryl group can be substituted or unsubstituted. When substituted, it can be substituted at any usable connection point. The substituent is selected from one or more of the following: deuterium, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxyl, alkylthio, haloalkylthio, cycloalkylthio, heterocyclic thio, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0378] The aforementioned cycloalkyl, heterocyclic, aryl, and heteroaryl groups include residues derived from removing one hydrogen atom from a parent ring atom, or residues derived from removing two hydrogen atoms from the same ring atom or two different ring atoms of the parent ring, i.e., "cycloalkylene", "heterocyclicene", "arylene", and "heteroarylene". Non-limiting examples include: wait.

[0379] When a polycyclic system formed by the fusion of a monocyclic heterocyclic group with a cycloalkyl, aryl, or heteroaryl group is divalent, the polycyclic system is considered a "fused heterocyclic group" as long as one of the linking sites is on the monocyclic heterocyclic group; non-limiting examples include:

[0380] The term "cycloalkylalkyl" refers to an alkyl group that is substituted by one or more cycloalkyl groups, wherein the cycloalkyl and alkyl groups are as defined above.

[0381] The term "heterocyclic alkyl" refers to an alkyl group that is substituted by one or more heterocyclic groups, wherein the heterocyclic group and the alkyl group are as defined above.

[0382] The term "arylalkyl" refers to an alkyl group that is substituted with one or more aryl groups, wherein the aryl and alkyl groups are as defined above.

[0383] The term "heteroarylalkyl" refers to an alkyl group that is substituted by one or more heteroaryl groups, wherein the heteroaryl and alkyl groups are as defined above.

[0384] The term "cycloalkylalkenyl" refers to an alkenyl group that is substituted by one or more cycloalkyl groups, wherein the cycloalkyl and alkenyl groups are as defined above.

[0385] The term "heterocyclic alkenyl" refers to an alkenyl group that is replaced by one or more heterocyclic groups, wherein the heterocyclic group and alkenyl group are as defined above.

[0386] The term "aryl-alkenyl" refers to an alkenyl group that is replaced by one or more aryl groups, where the aryl and alkenyl groups are as defined above.

[0387] The term "heteroaryl-alkenyl" refers to an alkenyl group that is substituted by one or more heteroaryl groups, wherein the heteroaryl and alkenyl groups are as defined above.

[0388] The term "cycloalkylynyl" refers to an ynyl group being replaced by one or more cycloalkyl groups, wherein the cycloalkyl and ynyl groups are as defined above.

[0389] The term "heterocyclic alkynyl" refers to an alkynyl group that is replaced by one or more heterocyclic groups, wherein the heterocyclic group and the alkynyl group are as defined above.

[0390] The term "aryl-alkynyl" refers to an alkynyl group being replaced by one or more aryl groups, where the aryl and alkynyl groups are as defined above.

[0391] The term "heteroaryl-alkynyl" refers to an alkynyl group being replaced by one or more heteroaryl groups, where the heteroaryl and alkynyl groups are as defined above.

[0392] The term "cycloalkyloxy" refers to -O-cycloalkyl, where the cycloalkyl is as defined above.

[0393] The term "heterocyclic oxygen group" refers to an -O-heterocyclic group, wherein the heterocyclic group is as defined above.

[0394] The term "aryloxy group" refers to -O-aryl, where the aryl group is as defined above.

[0395] The term "heteroaryloxy" refers to -O-heteroaryl, where the heteroaryl is as defined above.

[0396] The term "aminoalkyl" refers to an alkyl group that is substituted with one or more amino groups, wherein the alkyl group is as defined above.

[0397] The term "alkoxyalkyl" refers to an alkyl group that is substituted with one or more alkoxy groups, wherein the alkoxy groups and alkyl groups are as defined above.

[0398] The term "halogenated alkyl" refers to an alkyl group that has been substituted with one or more halogens, wherein the alkyl group is as defined above.

[0399] The term "haloalkoxy" refers to an alkoxy group that is substituted by one or more halogens, wherein the alkoxy group is as defined above.

[0400] The term "hydroxyalkyl" refers to an alkyl group that is replaced by one or more hydroxyl groups, wherein the alkyl group is as defined above.

[0401] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0402] The term "hydroxyl group" refers to -OH.

[0403] The term "thiol" refers to -SH.

[0404] The term "amino" refers to -NH2.

[0405] The term "cyano" refers to -CN.

[0406] The term "nitro" refers to -NO2.

[0407] The term "oxo" or "oxo group" refers to "=O".

[0408] The term "carbonyl" refers to C=O.

[0409] The term "alkylthio" refers to -S-alkyl, where the alkyl group is as defined above.

[0410] The term "haloalkylthio" refers to an alkylthio group that is replaced by one or more halogens, wherein the alkylthio group is as defined above.

[0411] The term "cycloalkylthio" refers to -S-cycloalkyl, where the cycloalkyl group is as defined above.

[0412] The term "heterocyclic thio" refers to a -S-heterocyclic group, where the heterocyclic group is as defined above.

[0413] A "leaving group," or simply a group, is an atom or functional group that breaks off from a larger molecule in a chemical reaction. It's a term used in nucleophilic substitution and elimination reactions. In a nucleophilic substitution reaction, the reactant attacked by the nucleophile is called the substrate, and the atom or group of atoms that breaks off with a pair of electrons from the substrate molecule is called the leaving group. Groups that readily accept electrons and have a strong ability to accept negative charges are desirable leaving groups. The smaller the pKa of the conjugate acid of the leaving group, the easier it is for the leaving group to break off from other molecules. This is because a smaller pKa means the leaving group doesn't need to bond with other atoms and has a stronger tendency to exist as an anion (or an electrically neutral leaving group). Common leaving groups include, but are not limited to, halogens, -OTs, or -OH.

[0414] The compounds disclosed herein can exist in specific stereoisomer forms. The term "stereoisomer" refers to isomers with the same structure but different spatial arrangements of atoms. These include cis and trans (or Z and E) isomers, (-)- and (+)- isomers, (R)- and (S)- enantiomers, diastereomers, (D)- and (L)- isomers, tautomers, blocked isomers, conformational isomers, and mixtures thereof (such as racemic mixtures and mixtures of diastereomers). Substituents in the compounds disclosed herein may contain additional asymmetric atoms. All such stereoisomers and mixtures thereof are included within the scope of this disclosure. Optically active (-)- and (+)- isomers, (R)- and (S)- enantiomers, and (D)- and (L)- isomers can be prepared by chiral synthesis, chiral reagents, or other conventional techniques. This disclosure discloses an isomer of a compound, which can be prepared by asymmetric synthesis or with chiral auxiliaries, or, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), by forming a salt of the diastereomer with a suitable optically active acid or base, followed by diastereomer resolution using conventional methods known in the art to obtain the pure isomer. Furthermore, the separation of enantiomers and diastereomers is typically performed by chromatography.

[0415] In the chemical structure of the compounds described in this disclosure, the bonds... This indicates that the configuration is not specified; that is, if chiral isomers exist in the chemical structure, the bond... It can be Or simultaneously include Two configurations. For all carbon-carbon double bonds, even if only one configuration is named, both the Z-type and E-type are included.

[0416] The compounds disclosed herein may exist in various tautomer forms, and all such forms are included within the scope of this disclosure. The terms "tautomer" or "tautomer form" refer to a structural isomer that exists in equilibrium and readily transforms from one isomer to another. This includes all possible tautomers, i.e., existing as a single isomer or as a mixture of said tautomers in any proportion. Non-limiting examples include: keto-enols, imine-enamines, lactam-lactamimides, etc. Examples of lactam-lactamimide equilibrium are shown below:

[0417] When referring to the pyrazolyl group, it should be understood to include any one or a mixture of two tautomers of the following two structures:

[0418] All tautomers are within the scope of this disclosure, and the naming of compounds does not exclude any tautomers.

[0419] The compounds disclosed herein may comprise transisomers. The term "transisomer" refers to a conformational stereoisomer resulting from restricted or significantly slowed rotation around a single bond in a molecule (as a result of steric interactions with other parts of the molecule and asymmetric substituents at the ends of the single bond), whose interconversion is slow enough to allow separation and isolation under predetermined conditions. For example, some compounds of this disclosure may exist as mixtures of transisomers (e.g., equal-proportion mixtures, mixtures enriched with one transisomer, etc.) or as a purified transisomer.

[0420] The compounds disclosed herein include all suitable isotopic derivatives thereof. The term "isotopic derivative" refers to a compound in which at least one atom is replaced by an atom having the same atomic number but a different atomic mass. Examples of isotopes that may be introduced into the compounds of this disclosure include stable and radioactive isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine, and iodine, for example, […]. 2 H (deuterium, D) 3 H (tritium, T) 11 C 13 C 14 C 15 N、 17 O、 18 O、 32 p、 33 p、 33 S, 34 S, 35 S, 36 S, 18 F, 36 Cl、 82 Br、 123 I,124 I, 125 I, 129 I and 131 In some implementations, I is deuterium.

[0421] Compared to undeuterated drugs, deuterated drugs offer advantages such as reduced toxicity, increased drug stability, enhanced efficacy, and prolonged biological half-life. All isotopic variations of the compounds disclosed herein, regardless of radioactivity, are included within the scope of this disclosure. Each available hydrogen atom bonded to a carbon atom can be independently replaced by a deuterium atom, wherein the deuterium substitution can be partial or complete; partial deuterium substitution refers to the replacement of at least one hydrogen atom with at least one deuterium atom.

[0422] When a position is specifically designated as deuterium (D), the position should be understood as having a deuterium abundance of at least 1,000 times greater than the natural abundance of deuterium (which is 0.015%) (i.e., at least 15% deuterium incorporation). The compounds in the examples having a natural abundance greater than deuterium can be at least 1000 times abundant deuterium (i.e., at least 15% deuterium doping), at least 2000 times abundant deuterium (i.e., at least 30% deuterium doping), at least 3000 times abundant deuterium (i.e., at least 45% deuterium doping), at least 3340 times abundant deuterium (i.e., at least 50.1% deuterium doping), at least 3500 times abundant deuterium (i.e., at least 52.5% deuterium doping), at least 4000 times abundant deuterium (i.e., at least 60% deuterium doping), or at least 4500 times abundant deuterium (i.e., at least 67.5% deuterium doping). The abundance of deuterium is at least 5000 times (i.e., at least 75% deuterium doping), at least 5500 times (i.e., at least 82.5% deuterium doping), at least 6000 times (i.e., at least 90% deuterium doping), at least 6333.3 times (i.e., at least 95% deuterium doping), at least 6466.7 times (i.e., at least 97% deuterium doping), at least 6600 times (i.e., at least 99% deuterium doping), at least 6633.3 times (i.e., at least 99.5% deuterium doping), or higher.

[0423] "Optional" or "optional" means that the event or situation described below may but is not necessarily to occur; it includes both the possibility that the event or situation may occur or not occur. For example, "C that is optionally substituted with a halogen or cyano group..." 1-6 "Alkyl" includes cases where the alkyl group is substituted with a halogen or cyano group and cases where the alkyl group is not substituted with a halogen or cyano group.

[0424] "Substitution" or "substituted" refers to one or more hydrogen atoms in a group, in some embodiments 1 to 6, and in some embodiments 1 to 3 hydrogen atoms, which are independently substituted by the corresponding number of substituents. Those skilled in the art can determine possible or impossible substitutions without much effort (through experimentation or theory). For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom having an unsaturated bond (such as an alkene).

[0425] "Pharmaceutical composition" means a mixture containing one or more of the compounds described herein or their pharmaceutically acceptable salts, along with other chemical components, such as pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to a living organism, thereby promoting the absorption of the active ingredient and its biological activity.

[0426] "Pharmacologically acceptable salt" refers to the salt of the compounds disclosed herein, which may be selected from inorganic or organic salts. Such salts are safe and effective when used in mammals and possess the expected biological activity. They can be prepared separately during the final isolation and purification of the compound, or by reacting a suitable group with a suitable base or acid. Bases commonly used to form pharmaceutically acceptable salts include inorganic bases, such as sodium hydroxide and potassium hydroxide, and organic bases, such as ammonia. Acids commonly used to form pharmaceutically acceptable salts include both inorganic and organic acids.

[0427] For the purposes of pharmaceuticals or pharmacologically active agents, the term "therapeutic effective amount" refers to the amount of a drug or agent sufficient to achieve or at least partially achieve the intended effect. The determination of the therapeutic effective amount varies from person to person, depending on the recipient's age and general condition, as well as the specific active substance. The appropriate therapeutic effective amount in a given case can be determined by a person skilled in the art based on routine testing.

[0428] As used herein, the term "pharmaceutically acceptable" means that these compounds, materials, compositions, and / or dosage forms are suitable for contact with patient tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, within reasonable medical judgment, have a reasonable benefit / risk ratio, and are effective for their intended use.

[0429] As used herein, the singular forms of “a,” “an,” and “the” include plural references, and vice versa, unless the context clearly indicates otherwise.

[0430] When the term "about" is applied to parameters such as pH, concentration, temperature, etc., it indicates that the parameter can vary by ±10%, and in some embodiments within ±5%. As those skilled in the art will understand, when a parameter is not critical, figures are typically given for illustrative purposes only and not as limitations. Detailed Implementation

[0431] The following embodiments are used to further describe this disclosure, but these embodiments are not intended to limit the scope of this disclosure.

[0432] Example

[0433] The structure of the compound was determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts (δ) were expressed in 10⁻¹⁰. -6 The unit (ppm) is given. NMR determination was performed using a Bruker AVANCE-400 NMR spectrometer or a Bruker AVANCE NEO 500M. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD). The internal standard was tetramethylsilane (TMS).

[0434] MS measurements were performed using an Agilent 1200 / 1290DAD-6110 / 6120 Quadrupole MS LC-MS system (manufacturer: Agilent, MS model: 6110 / 6120 Quadrupole MS), a Waters ACQuity UPLC-QD / SQD system (manufacturer: Waters, MS model: Waters ACQuity Qda Detector / Waters SQ Detector), and a THERMO Ultimate 3000-Q Exactive system (manufacturer: THERMO, MS model: THERMO Q Exactive).

[0435] High-performance liquid chromatography (HPLC) analysis was performed using an Agilent HPLC 1200DAD, an Agilent HPLC 1200VWD, and a Waters HPLC e2695-2489 high-performance liquid chromatograph.

[0436] Chiral HPLC analysis was performed using an Agilent 1260DAD high-performance liquid chromatograph.

[0437] High performance liquid chromatography (HPLC) was performed using Waters 2545-2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP, and Gilson GX-281 preparative chromatographs.

[0438] Chiral preparative chromatography was performed using a Shimadzu LC-20AP preparative chromatograph.

[0439] The CombiFlash rapid preparation system uses a CombiFlash Rf200 (TELEDYNE ISCO).

[0440] Thin-layer chromatography silica gel plates are Yantai Huanghai HSGF254 or Qingdao GF254. The silica gel plates used in thin-layer chromatography (TLC) have a diameter of 0.15 mm to 0.2 mm, and the diameter of the silica gel plates used for thin-layer chromatography separation and purification products is 0.4 mm to 0.5 mm.

[0441] Silica gel column chromatography generally uses Yantai Huanghai silica gel with a mesh size of 200-300 as the carrier.

[0442] Mean inhibition rate of kinases and IC 50 The values ​​were determined using a NovoStar microplate reader (BMG GmbH, Germany).

[0443] The known starting materials disclosed herein can be synthesized using or in accordance with methods known in the art, or can be purchased from companies such as ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, and Darui Chemicals.

[0444] Unless otherwise specified in the examples, all reactions can be carried out under an argon or nitrogen atmosphere.

[0445] Argon or nitrogen atmosphere refers to a reaction flask connected to an argon or nitrogen gas balloon with a volume of approximately 1L.

[0446] A hydrogen atmosphere refers to a reaction flask connected to a hydrogen balloon with a volume of approximately 1L.

[0447] The pressurized hydrogenation reaction was performed using a Parr 3916EKX hydrogenator and a Qinglan QL-500 hydrogen generator or an HC2-SS hydrogenator.

[0448] The hydrogenation reaction is usually carried out under vacuum, filled with hydrogen gas, and repeated 3 times.

[0449] The microwave reaction was performed using a CEM Discover-S 908860 microwave reactor.

[0450] Unless otherwise specified in the examples, "solution" refers to an aqueous solution.

[0451] Unless otherwise specified in the examples, the reaction temperature is room temperature.

[0452] The reaction process in the examples was monitored using thin-layer chromatography (TLC). The developing solvent used in the reaction, the eluent system for column chromatography used to purify the compounds, and the developing solvent system for TLC included: A: dichloromethane / methanol system, B: n-hexane / ethyl acetate system, C: petroleum ether / ethyl acetate system, D: dichloromethane:ethyl acetate, E: ethyl acetate:methanol. The volume ratio of the solvent was adjusted according to the polarity of the compounds, and small amounts of basic or acidic reagents such as triethylamine and acetic acid could also be added for adjustment.

[0453] Example 1

[0454] (1S,2S)-N-((6 3 S,4S,Z)-1 1 -Ethyl-1 2 -(8-((S)-1-methoxyethyl)-3-methyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-d]pyridino[2,3-b][1,4]oxazin-9-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazo-1(5,3)-indolaz-6(1,3)-pyridazine-cycloundecaban-4-yl)-2-methylcyclopropane-1-formamide

[0455] M-(1S,2S)-N-((6 3 S,4S,Z)-1 1 -Ethyl-1 2 -((S)-8-((S)-1-methoxyethyl)-3-methyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-d]pyrido[2,3-b][1,4]oxazin-9-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazo-1(5,3)-indolaz-6(1,3)-pyridazine-cycloundecafen-4-yl)-2-methylcyclopropane-1-carboxamide 1-p1

[0456] M-(1S,2S)-N-((6 3 S,4S,Z)-1 1 -Ethyl-12 -((R)-8-((S)-1-methoxyethyl)-3-methyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-d]pyrido[2,3-b][1,4]oxazin-9-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazo-1(5,3)-indolaz-6(1,3)-pyridazine-cycloundecaban-4-yl)-2-methylcyclopropane-1-carboxamide 1-p2

[0457] P-(1S,2S)-N-((6 3 S,4S,Z)-1 1 -Ethyl-1 2 -((S)-8-((S)-1-methoxyethyl)-3-methyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-d]pyrido[2,3-b][1,4]oxazin-9-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazo-1(5,3)-indolaz-6(1,3)-pyridazine-cycloundecafen-4-yl)-2-methylcyclopropane-1-carboxamide 1-p3

[0458] P-(1S,2S)-N-((6 3 S,4S,Z)-1 1 -Ethyl-1 2 -((R)-8-((S)-1-methoxyethyl)-3-methyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-d]pyrido[2,3-b][1,4]oxazin-9-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazo-1(5,3)-indolaz-6(1,3)-pyridazine-cycloundecafen-4-yl)-2-methylcyclopropane-1-carboxamide 1-p4

[0459] first step

[0460] (S)-1-(5-bromopyridin-2-yl)ethanol-1-ol 1b

[0461] Formic acid (5.64 g, 120.09 mmol) was added to triethylamine (61.23 g, 605.15 mmol), and (S,S)-N-(p-toluenesulfonyl)-1,2-diphenylethanediamine (p-isopropylbenzene)ruthenium(II) chloride (318 mg, 499.83 μmol, Shanghai Titan) was added at 0 °C. The reaction was carried out at 40 °C for 15 minutes under a nitrogen atmosphere. After cooling to room temperature, 2-acetyl-5-bromopyridine 1a (10 g, 50 mmol, Shanghai Shaoyuan) was added, and the reaction was carried out at 40 °C for 2 hours under a nitrogen atmosphere. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate. The organic phase was separated by washing with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to give title compound 1b (10 g, yield: 99%).

[0462] Step 2

[0463] (S)-5-bromo-2-(1-methoxyethyl)pyridine 1c

[0464] Compound 1b (9.9 g, 49 mmol) was dissolved in N,N-dimethylformamide (100 mL), and sodium hydride (2.35 g, 58.76 mmol, 60% purity) was added at 0 °C. The mixture was stirred for 1 hour while maintaining the temperature. Iodomethane (13.91 g, 98 mmol) was added, and the mixture was stirred for 2 hours after returning to room temperature. The reaction mixture was quenched with saturated ammonium chloride aqueous solution, and extracted with ethyl acetate (100 mL × 3). The organic phases were combined and washed successively with water and saturated sodium chloride solution. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system B to give title compound 1c (8.5 g, yield: 80%).

[0465] Step 3

[0466] (S)-5-bromo-2-(1-methoxyethyl)pyridine 1-oxide 1d

[0467] Compound 1c (3.38 g, 15.64 mmol) was dissolved in dichloromethane (50 mL), and m-chloroperoxybenzoic acid (4.76 g, 23.44 mmol, 85% purity) was added. The mixture was stirred for 16 hours. The reaction solution was quenched with saturated sodium bicarbonate and sodium sulfite aqueous solutions, and extracted with dichloromethane (50 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system D to give the title compound 1d (3.1 g, yield: 85.4%).

[0468] MS m / z(ESI):232.0[M+1].

[0469] Step 4

[0470] (S)-3-bromo-6-(1-methoxyethyl)pyridine-2-ylacetate 1e

[0471] Compound 1d (4.13 g, 17.8 mmol) was dissolved in acetic anhydride (25 mL), and the mixture was heated to 135 °C and stirred for 16 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was adjusted to pH > 7 with saturated sodium bicarbonate solution, extracted with dichloromethane (50 mL × 3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system B to give the title compound 1e (3.6 g, yield: 73.8%).

[0472] MS m / z(ESI):274.0[M+1].

[0473] Step 5

[0474] (S)-3-bromo-6-(1-methoxyethyl)pyridine-2-phenol 1f

[0475] Compound 1e (3.6 g, 13.13 mmol) was dissolved in methanol (25 mL), and lithium hydroxide monohydrate (661 mg, 15.75 mmol) was added. The mixture was stirred for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was adjusted to pH < 7 with 1 M hydrochloric acid. It was extracted with dichloromethane (50 mL × 3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system D to give the title compound 1f (2.81 g, yield: 92.2%).

[0476] MS m / z(ESI):232.1[M+1].

[0477] Step 6

[0478] (S)-3,5-dibromo-6-(1-methoxyethyl)pyridine-2-phenol 1g

[0479] Compound 1f (2.81 g, 12.11 mmol) was dissolved in acetonitrile (40 mL), and N-bromosuccinimide (NBS) (2.26 g, 12.71 mmol) was added. The mixture was stirred for 2 hours. The reaction solution was quenched with saturated sodium sulfite and saturated sodium bicarbonate solutions, and extracted with dichloromethane (50 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system D to give compound 1f (3.6 g, yield: 95.6%).

[0480] MS m / z(ESI):310.0[M+1].

[0481] Step 7

[0482] 4-Benzyl-1-(tert-butyl)2-(((3,5-dibromo-6-((S)-1-methoxyethyl)pyridin-2-yl)oxy)methyl)piperazine

[0483] -1,4-dicarboxylic acid ester 1h

[0484] 4-Benzyl-1-(tert-butyl)-2-(hydroxymethyl)piperazine-1,4-dicarboxylic acid ester (4.47 g, 12.76 mmol, prepared by the method disclosed in Example 143 on page 168 of patent application "WO2013188856"), 1 g of compound (3.67 g, 11.8 mmol), and triphenylphosphine (4.65 g, 17.72 mmol) were dissolved in tetrahydrofuran (60 mL). Under a nitrogen atmosphere and in an ice bath, diisopropyl azodicarbonate (3.58 g, 17.7 mmol) was added dropwise, and the reaction was allowed to return to room temperature for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system B to give the title compound 1h (7.56 g, yield: 99%).

[0485] Step 8

[0486] 3-(((3,5-dibromo-6-((S)-1-methoxyethyl)pyridin-2-yl)oxy)methyl)piperazine-1-carboxylic acid benzyl ester 1i

[0487] Compound 1h (7.56 g, 11.75 mmol) was dissolved in dichloromethane (20 mL), and trifluoroacetic acid (10 mL) was added. The mixture was stirred for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was adjusted to pH > 7 with saturated sodium bicarbonate aqueous solution. It was extracted with dichloromethane (100 mL × 3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system E to give the title compound 1i (4.9 g, yield: 77.3%).

[0488] MS m / z(ESI): 542.2 [M+1].

[0489] Step 9

[0490] 9-Bromo-8-((S)-1-methoxyethyl)-1,2,4a,5-tetrahydropyrazino[1,2-d]pyridino[2,3-b][1,4]oxazine-3(4H)-

[0491] benzyl carboxylate 1j

[0492] Compound 1i (4.9 g, 9.08 mmol) was dissolved in 1,4-dioxane (100 mL), and methanesulfonic acid (9,9-dimethyl-4,5-bisdiphenylphosphineoxanthracene)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (862 mg, 908.94 μmol) and cesium carbonate (7.4 g, 22.7120 mmol) were added. The mixture was heated to 105 °C for 16 hours under a nitrogen atmosphere. After the reaction solution was cooled to room temperature, it was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system D to give title compound 1j (3.42 g, yield: 81.3%).

[0493] MS m / z(ESI):462.2[M+1].

[0494] Step 10

[0495] 8-((S)-1-methoxyethyl)-9-(4,4,5,5-tetramethyl-1,3,2-dioxoborhexacyclopentan-2-yl)-1,2,4a,5-tetrahydropyrazino[1,2-d]pyrido[2,3-b][1,4]oxazine-3(4H)-carboxylic acid benzyl ester 1k

[0496] Compound 1j (2.97 g, 6.42 mmol), potassium acetate (3.15 g, 32.1 mmol), pinacol diboronate (4.9 g, 19.3 mmol), and 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (470 mg, 642.3 μmol) were dissolved in toluene (15 mL). The mixture was heated to 100 °C and reacted for 16 hours under a nitrogen atmosphere. After the reaction solution was cooled to room temperature, it was filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to give the title compound 1k (2.1 g, yield: 64.1%).

[0497] MS m / z(ESI): 510.4 [M+1].

[0498] Step 11

[0499] (S)-1-((S)-2-((tert-butoxycarbonyl)amino)-3-(4-(3-(3-hydroxy-2,2-dimethylpropyl)-2-iodo-1H-indol-5-yl)thiazolyl)propionyl)hexahydropyridazine-3-carboxylic acid methyl ester 1n

[0500] 1 mL (2.09 g, 5.61 mmol, Shanghai Bide) of methyl (S)-hexahydropyridazine-3-carboxylate bis(2,2,2-trifluoroacetate) was dissolved in dichloromethane (50 mL), and 1 L (1.35 g, 2.25 mmol, of (S)-2-((tert-butoxycarbonyl)amino)-3-(4-(3-(3-hydroxy-2,2-dimethylpropyl)-2-iodo-1H-indol-5-yl)thiazolyl-2-yl)propionic acid was added, using the Intermediate method described on page 291 of patent application "WO2022060836". The compound was prepared by the disclosed method. N-methylmorpholine (4.56 g, 45.08 mmol) was added at 0 °C, followed by the addition of 1-hydroxybenzotriazole (192 mg, 1.26 mmol) and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.41 g, 7.35 mmol). The mixture was stirred at room temperature for 5 hours. The reaction mixture was quenched with saturated sodium bicarbonate solution, extracted with dichloromethane (40 mL × 3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system A to give the title compound 1n (1.16 g, yield: 71%).

[0501] MS m / z(ESI): 726.5 [M+1].

[0502] Step Twelve

[0503] (S)-1-((S)-2-((tert-butoxycarbonyl)amino)-3-(4-(3-(3-hydroxy-2,2-dimethylpropyl)-2-iodo-1H-indol-5-yl)thiazolyl)propionyl)hexahydropyridazine-3-carboxylic acid 1o

[0504] Compound 1n (1.16 g, 1.6 mmol) was dissolved in tetrahydrofuran (10 mL), and a solution of lithium hydroxide monohydrate (291.46 mg, 6.94 mmol) in water (6.5 mL) was added at 0 °C. The mixture was allowed to return to room temperature naturally with stirring for 1 hour. The pH of the reaction solution was adjusted to <7 with 1 M hydrochloric acid, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title compound 1o (1.2 g). The product was used directly in the next reaction without purification.

[0505] MS m / z(ESI):712.4[M+1].

[0506] Step 13 (6) 3 S,4S,Z)-12-iodo-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazo-1(5,3)-indolaz-6(1,3)-pyridazine-cycloundecafen-4-yl) tert-butyl carbamate 1p

[0507] The crude title compound 1o (1.2 g, 1.71 mmol) was dissolved in dichloromethane (50 mL), and 1-hydroxybenzotriazole (1.3 g, 8.54 mmol) and N,N-diisopropylethylamine (6.7 g, 51.8 mmol) were added. The mixture was cooled to 0 °C, and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (6.6 g, 34.4 mmol) was added in portions. The mixture was stirred at room temperature for 16 hours. The reaction solution was quenched with saturated sodium bicarbonate solution, and extracted with dichloromethane (30 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to give title compound 1p (710 mg, yield: 59.5%).

[0508] MS m / z(ESI): 694.5 [M+1].

[0509] Step Fourteen

[0510] 9-((6 3 S,4S,Z)-4-((tert-butoxycarbonyl)amino)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazo-1(5,3)-indolazo-6(1,3)-pyridazine-cycloundecaban-12-yl)-8-((S)-1-methoxyethyl)-1,2,4a,5-tetrahydropyrazino[1,2-d]pyrido[2,3-b][1,4]oxazine-3(4H)-carboxylic acid benzyl ester 1q

[0511] Compound 1k (110 mg, 215.9 μmol), compound 1p (100 mg, 144.1 μmol), 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (11 mg, 15 μmol), and potassium phosphate (92 mg, 433.4 μmol) were dissolved in toluene (9 mL), 1,4-dioxane (3 mL), and water (3 mL). The reaction was carried out at 85 °C for 1 hour under a nitrogen atmosphere. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in dichloromethane. Water was added, and the mixture was extracted with dichloromethane (15 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered to remove the desiccant, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to give title compound 1q (113 mg, yield: 82.5%).

[0512] MS m / z(ESI): 949.7 [M+1].

[0513] Step 15

[0514] 9-((6 3 S,4S,Z)-4-((tert-butoxycarbonyl)amino)-1 1 -Ethyl-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazo-1(5,3)-indolazo-6(1,3)-pyridazine-cycloundecaban-12-yl)-8-((S)-1-methoxyethyl)-1,2,4a,5-tetrahydropyrazino[1,2-d]pyrido[2,3-b][1,4]oxazine-3(4H)-carboxylic acid benzyl ester 1r

[0515] Compound 1q (113 mg, 119.05 μmol) was dissolved in N,N-dimethylformamide (10 mL), cesium carbonate (117 mg, 359.1 μmol) was added, the mixture was cooled to 0 °C, iodoethane (32 mg, 205.1 μmol) was added, and the mixture was stirred at room temperature for 4.5 h. The reaction mixture was diluted with ethyl acetate and filtered. The filtrate was washed successively with water and saturated sodium chloride solution to separate the organic phase. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin-layer silica gel chromatography using solvent system A to give the title compound 1r (106 mg, yield: 91.1%). MS m / z (ESI): 977.8 [M+1].

[0516] Step Sixteen

[0517] ((6 3S,4S,Z)-1 1 -Ethyl-1 2 -(8-((S)-1-methoxyethyl)-1,2,3,4,4a,5-hexahydropyrazino[1,2-d]pyridino[2,3-b][1,4]oxazin-9-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazo-1(5,3)-indolaz-6(1,3)-pyridazine-cycloundecafen-4-yl) tert-butyl carbamate 1s

[0518] Compound 1r (106 mg, 108.47 μmol) was dissolved in methanol (20 mL), paraformaldehyde (33 mg, 1.1 mmol) and palladium hydroxide on carbon (wet) (106 mg) were added, and the mixture was stirred for 3 hours. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by thin-layer silica gel chromatography with solvent system A to give the title compound 1s (61 mg, yield: 67%).

[0519] MS m / z(ESI): 843.7 [M+1].

[0520] Step 17 ((6) 3 S,4S,Z)-1 1 -Ethyl-1 2 -(8-((S)-1-methoxyethyl)-3-methyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-d]pyridino[2,3-b][1,4]oxazin-9-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazo-1(5,3)-indolaz-6(1,3)-pyridazine-cycloundecafen-4-yl) tert-butyl carbamate 1t

[0521] Compound 1s (61 mg, 72.35 μmol) was dissolved in methanol (10 mL), and 37% formaldehyde aqueous solution (12 mg, 147.8 μmol), acetic acid (13 mg, 216.4 μmol), and sodium cyanoborohydride (6 mg, 95.5 μmol) were added. The mixture was stirred for 2 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate (15 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered to remove the drying agent, and concentrated under reduced pressure. The residue was purified by thin-layer silica gel chromatography using solvent system A to give the title compound 1t (83 mg, yield: 133.8%).

[0522] MS m / z(ESI): 857.7 [M+1].

[0523] Step 18 (6) 3 (S,4S,Z)-4-amino-1 1 -Ethyl-1 2 -(8-((S)-1-methoxyethyl)-3-methyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-d]pyridino[2,3-b][1,4]oxazin-9-yl)-10,10-dimethyl-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazo-1(5,3)-indolaz-6(1,3)-pyridazine-cycloundecaban-5,7-dionebis(2,2,2-trifluoroacetate)1u

[0524] Compound 1t (83 mg, 96.84 μmol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (0.5 mL) was added at 0 °C. The mixture was stirred for 2 hours, and the reaction solution was concentrated under reduced pressure to obtain crude title compound 1u (160 mg). The product was used directly in the next reaction without purification.

[0525] MS m / z(ESI): 757.7 [M+1].

[0526] Step 19

[0527] (1S,2S)-N-((6 3 S,4S,Z)-1 1 -Ethyl-1 2 -(8-((S)-1-methoxyethyl)-3-methyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-d]pyridino[2,3-b][1,4]oxazin-9-yl)-10,10-dimethyl-5,7-dioxo-6 16 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazo-1(5,3)-indolaz-6(1,3)-pyridazine-cycloundecaban-4-yl)-2-methylcyclopropane-1-formamide

[0528] M-(1S,2S)-N-((6 3 S,4S,Z)-1 1 -Ethyl-1 2 -((S)-8-((S)-1-methoxyethyl)-3-methyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-d]pyrido[2,3-b][1,4]oxazin-9-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazo-1(5,3)-indolaz-6(1,3)-pyridazine-cycloundecafen-4-yl)-2-methylcyclopropane-1-carboxamide 1-p1

[0529] M-(1S,2S)-N-((6 3 S,4S,Z)-1 1 -Ethyl-1 2 -((R)-8-((S)-1-methoxyethyl)-3-methyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-d]pyrido[2,3-b][1,4]oxazin-9-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazo-1(5,3)-indolaz-6(1,3)-pyridazine-cycloundecaban-4-yl)-2-methylcyclopropane-1-carboxamide 1-p2

[0530] P-(1S,2S)-N-((6 3 S,4S,Z)-1 1 -Ethyl-1 2-((S)-8-((S)-1-methoxyethyl)-3-methyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-d]pyrido[2,3-b][1,4]oxazin-9-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazo-1(5,3)-indolaz-6(1,3)-pyridazine-cycloundecafen-4-yl)-2-methylcyclopropane-1-carboxamide 1-p3

[0531] P-(1S,2S)-N-((6 3 S,4S,Z)-1 1 -Ethyl-1 2 -((R)-8-((S)-1-methoxyethyl)-3-methyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-d]pyrido[2,3-b][1,4]oxazin-9-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazo-1(5,3)-indolaz-6(1,3)-pyridazine-cycloundecafen-4-yl)-2-methylcyclopropane-1-carboxamide 1-p4

[0532] Crude compound 1u (160 mg, 162.5 μmol) was dissolved in N,N-dimethylformamide (8 mL), and N,N-diisopropylethylamine (1.46 g, 11.28 mmol) was added. (1S,2S)-2-methylcyclopropane-1-carboxylic acid (30 mg, 299.6539 μmol, Shanghai Bide) and 1-cyano-2-ethoxy-2-oxoethyleneaminooxy)dimethylamino-morpholino-carbomony hexafluorophosphate (50 mg, 211.37 μmol, Shanghai Shaoyuan) were added at 0 °C, and the mixture was stirred for 2 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain crude compound 1 (100 mg). Purification was performed by preparative high-performance liquid chromatography (Waters-2545, column: Welch Xtimate C18, 30×150mm, 5μm; mobile phase: aqueous phase (10mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 40%-60%, flow rate: 30mL / min) to give two of the title compounds (10mg, yield: 10%), (5mg, yield: 5%), and a mixture of two other isomers (12mg, yield: 12%).

[0533] Single configuration compound (shorter retention time): (10 mg, yield: 10%).

[0534] MS m / z(ESI): 839.8 [M+1].

[0535] HPLC analysis: retention time 1.43 min, purity: 99% (column: Ultimate, C18, 1.8 μm, 2.1*50 mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%).

[0536] 1H NMR (500MHz, CD3OD): δ8.56(s,1H),7.69(dd,1H),7.55(s,1H),7.45(d,1H),7.25(s,1H),5.68(d,1H),4.80(d,1H),4.52(d d,1H),4.47-4.45(m,1H),4.31(td,1H),4.25(dd,1H),4.11-4.09(m,1H),3.96(q,1H),3.85-3.80(m,1H),3.80-3.71(m,3H) ,3.48-3.45(m,1H),3.31-3.28(m,3H),3.24(s,2H),3.19-3.16(m,1H),3.01-2.99(m,2H),2.86(td,1H),2.79(td,1H),2.4 8(d,1H),2.40(s,3H),2.31-2.27(m,2H),2.00-1.85(m,3H),1.67-1.62(qd,1H),1.55-1.51(m,1H),1.32-1.29(m,5H),1.20 -1.16(m,4H),1.15-1.10(m,1H),1.04(s,3H),0.69-0.66(m,1H),0.64(s,3H).

[0537] Single-configuration compound (longer retention time): (5 mg, yield: 5%).

[0538] MS m / z(ESI): 839.8 [M+1].

[0539] HPLC analysis: Retention time 1.46 min, purity: 99% (Column: ACQUITY) C18, 1.7μm, 2.1*50mm; Mobile phase: water (10mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%).

[0540] 1H NMR (500MHz, CD3OD): δ8.55(s,1H),7.69(dd,1H),7.55(s,1H),7.47(d,1H),7.13(s,1H),5.78(s,1H),4.52(dd,1H),4.47-4.44(m,1H) ,4.34-4.28(m,3H),4.26-4.15(m,1H),3.77-3.71(m,3H),3.47-3.43(m,2H),3.31-3.25(m,2H),3.07(d,1H),2.99(d,2H),2.28-2.77(m ,2H),2.60(d,1H),2.40(s,3H),2.31(td,1H),2.21-2.18(m,1H),1.97-1.92(m,1H),1.81-1.75(m,2H),1.62(qd,2H),1.53-1.48(m,1H) ,1.40(d,3H),1.36-1.33(m,2H),1.28-1.23(m,2H),1.14(d,3H),1.12-1.08(m,1H),1.04-0.98(m,5H),0.67-0.64(m,1H),0.56(s,3H).

[0541] Mixture of the two isomers (longest retention time): (12 mg, yield: 12%).

[0542] MS m / z(ESI): 839.8 [M+1].

[0543] HPLC analysis: Retention time 1.50 min, purity: 99% (Column: ACQUITY) C18, 1.7μm, 2.1*50mm; Mobile phase: water (10mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%).

[0544] 1H NMR (500MHz, CD3OD): δ8.55(s,1H),7.68(s,1H),7.55(s,1H),7.48-7.44(m,1H),7.26-7.16(m,1H),5.79-5.67(m,1H),4.54-4.51( m,1H),4.47-4.41(m,1H),4.34-4.28(m,1H),4.26-4.17(m,2H),4.10-4.03(m,1H),3.93(q,1H),3.84-3.71(m,4H),3.48-3.43(m,1H ),3.31-3.20(m,3H),3.19-3.16(m,3H),3.09-2.98(m,2H),2.85-2.74(m,3H),2.45-2.42(m,1H),2.39(s,2H),2.33-2.28(m,2H),2 .00-1.85(m,3H),1.67-1.60(m,1H),1.55-1.49(m,1H),1.37-1.23(m,6H),1.16-1.08(m,4H),1.04-0.98(m,3H),0.69-0.54(m,4H).

[0545] Example 2

[0546] (1S,2S)-N-((6 4 S,4S,Z)-1 1 -Ethyl-1 2 -(8-((S)-1-methoxyethyl)-3-methyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-d]pyridino[2,3-b][1,4]oxazin-9-yl)-10,10-dimethyl-5,7-dioxo-1 1 H-8-Oza-6 2 6 3 -diaza-2(4,2)-thiazo-1(5,3)-indolaza-6(2,4)-bicyclo[3.1.1]heptaneheterocyclic undecaban-4-yl)-2-methylcyclopropane-1-carboxamide 2

[0547] M-(1S,2S)-N-((6 4 S,4S,Z)-1 1 -Ethyl-1 2 -((S)-8-((S)-1-methoxyethyl)-3-methyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-d]pyrido[2,3-b][1,4]oxazin-9-yl)-10,10-dimethyl-5,7-dioxo-1 1 H-8-Oza-6 2 63 -diaza-2(4,2)-thiazo-1(5,3)-indolaza-6(2,4)-bicyclo[3.1.1]heptaneheterocyclic undecaban-4-yl)-2-methylcyclopropane-1-carboxamide 2-p1

[0548] M-(1S,2S)-N-((6 4 S,4S,Z)-1 1 -Ethyl-1 2 -((R)-8-((S)-1-methoxyethyl)-3-methyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-d]pyrido[2,3-b][1,4]oxazin-9-yl)-10,10-dimethyl-5,7-dioxo-1 1 H-8-Oza-6 2 6 3 -diaza-2(4,2)-thiazo-1(5,3)-indolaza-6(2,4)-bicyclo[3.1.1]heptaneheterocyclic undecaban-4-yl)-2-methylcyclopropane-1-carboxamide 2-p2

[0549] P-(1S,2S)-N-((6 4 S,4S,Z)-1 1 -Ethyl-1 2 -((S)-8-((S)-1-methoxyethyl)-3-methyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-d]pyrido[2,3-b][1,4]oxazin-9-yl)-10,10-dimethyl-5,7-dioxo-1 1 H-8-Oza-6 2 6 3 -diaza-2(4,2)-thiazo-1(5,3)-indolaza-6(2,4)-bicyclo[3.1.1]heptaneheptan-1 / 2-yl)-2-methylcyclopropane-1-carboxamide 2-p3

[0550] P-(1S,2S)-N-((6 4 S,4S,Z)-1 1 -Ethyl-1 2 -((R)-8-((S)-1-methoxyethyl)-3-methyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-d]pyrido[2,3-b][1,4]oxazin-9-yl)-10,10-dimethyl-5,7-dioxo-1 1 H-8-Oza-6 2 6 3-diaza-2(4,2)-thiazo-1(5,3)-indolaza-6(2,4)-bicyclo[3.1.1]heptaneheterocyclic undecaban-4-yl)-2-methylcyclopropane-1-carboxamide 2-p4

[0551] Using the synthetic route in Example 1, the starting compound 1m in step eleven was replaced with methyl (S)-2,3-diazabicyclo[3.1.1]heptane-4-carboxylic acid (prepared by the method disclosed in Reference Example 6 on page 61 of the specification in patent application "WO2024067857") to obtain the title compound.

[0552] MS m / z(ESI): 851.4 [M+1].

[0553] Example 3

[0554] (1S,2S)-N-((6 4 S,4S,Z)-1 1 -Ethyl-1 2 -(9-((S)-1-methoxyethyl)-3-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyridino[3,2-e][1,4]oxazopentane-10-yl)-10,10-dimethyl-5,7-dioxo-1 1 H-8-Oza-6 2 6 3 -diaza-2(4,2)-thiazo-1(5,3)-indolaza-6(2,4)-bicyclo[3.1.1]heptaneheterocyclic undecaban-4-yl)-2-methylcyclopropane-1-carboxamide 3

[0555] M-(1S,2S)-N-((6 4 S,4S,Z)-1 1 -Ethyl-1 2 -((S)-9-((S)-1-methoxyethyl)-3-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyridino[3,2-e][1,4]oxazopentane-10-yl)-10,10-dimethyl-5,7-dioxo-1 1 H-8-Oza-6 2 6 3 -diaza-2(4,2)-thiazo-1(5,3)-indolaza-6(2,4)-bicyclo[3.1.1]heptaneheterocyclic undecaban-4-yl)-2-methylcyclopropane-1-carboxamide 3-p1

[0556] M-(1S,2S)-N-((6 4 S,4S,Z)-11 -Ethyl-1 2 -((R)-9-((S)-1-methoxyethyl)-3-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyridino[3,2-e][1,4]oxazopentane-10-yl)-10,10-dimethyl-5,7-dioxo-1 1 H-8-Oza-6 2 6 3 -diaza-2(4,2)-thiazo-1(5,3)-indolaza-6(2,4)-bicyclo[3.1.1]heptaneheterocyclic undecaban-4-yl)-2-methylcyclopropane-1-carboxamide 3-p2

[0557] P-(1S,2S)-N-((6 4 S,4S,Z)-1 1 -Ethyl-1 2 -((S)-9-((S)-1-methoxyethyl)-3-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyridino[3,2-e][1,4]oxazopentane-10-yl)-10,10-dimethyl-5,7-dioxo-1 1 H-8-Oza-6 2 6 3 -diaza-2(4,2)-thiazo-1(5,3)-indolaza-6(2,4)-bicyclo[3.1.1]heptaneheterocyclic undecaban-4-yl)-2-methylcyclopropane-1-carboxamide 3-p3

[0558] P-(1S,2S)-N-((6 4 S,4S,Z)-1 1 -Ethyl-1 2 -((R)-9-((S)-1-methoxyethyl)-3-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyridino[3,2-e][1,4]oxazopentane-10-yl)-10,10-dimethyl-5,7-dioxo-1 1 H-8-Oza-6 2 6 3 -diaza-2(4,2)-thiazo-1(5,3)-indolaza-6(2,4)-bicyclo[3.1.1]heptaneheterocyclic undecaban-4-yl)-2-methylcyclopropane-1-carboxamide 3-p4

[0559] MS m / z(ESI): 865.4 [M+1].

[0560] Example 4

[0561] (1S,2S)-N-((6 3 S,4S,Z)-1 1 -Ethyl-1 6 -Fluorine-1 2 -(8-((S)-1-methoxyethyl)-3-methyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-d]pyridino[2,3-b][1,4]oxazin-9-yl-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazo-1(5,3)-indolaz-6(1,3)-pyridazine-cycloundecaban-4-yl)-2-methylcyclopropane-1-carboxamide 4

[0562] M-(1S,2S)-N-((6 3 S,4S,Z)-1 1 -Ethyl-1 6 -Fluorine-1 2 -((S)-8-((S)-1-methoxyethyl)-3-methyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-d]pyrido[2,3-b][1,4]oxazin-9-yl-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazo-1(5,3)-indolaz-6(1,3)-pyridazine-cycloundecafen-4-yl)-2-methylcyclopropane-1-carboxamide 4-p1

[0563] M-(1S,2S)-N-((6 3 S,4S,Z)-1 1 -Ethyl-1 6 -Fluorine-1 2 -((R)-8-((S)-1-methoxyethyl)-3-methyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-d]pyrido[2,3-b][1,4]oxazin-9-yl-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 65 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazo-1(5,3)-indolaz-6(1,3)-pyridazine-cycloundecafen-4-yl)-2-methylcyclopropane-1-carboxamide 4-p2

[0564] P-(1S,2S)-N-((6 3 S,4S,Z)-1 1 -Ethyl-1 6 -Fluorine-1 2 -((S)-8-((S)-1-methoxyethyl)-3-methyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-d]pyrido[2,3-b][1,4]oxazin-9-yl-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazo-1(5,3)-indolaz-6(1,3)-pyridazine-cycloundecafen-4-yl)-2-methylcyclopropane-1-carboxamide 4-p3

[0565] P-(1S,2S)-N-((6 3 S,4S,Z)-1 1 -Ethyl-1 6 -Fluorine-1 2 -((R)-8-((S)-1-methoxyethyl)-3-methyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-d]pyrido[2,3-b][1,4]oxazin-9-yl-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazo-1(5,3)-indolaz-6(1,3)-pyridazine-cycloundecaban-4-yl)-2-methylcyclopropane-1-carboxamide 4-p4

[0566] MS m / z(ESI): 857.4 [M+1].

[0567] Example 5

[0568] (1S,2S)-N-((63 S,4S,Z)-1 1 -Ethyl-1 4 -Fluorine-1 2 -(8-((S)-1-methoxyethyl)-3-methyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-d]pyridino[2,3-b][1,4]oxazin-9-yl-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazo-1(5,3)-indolaz-6(1,3)-pyridazine-cycloundecaban-4-yl)-2-methylcyclopropane-1-carboxamide 5

[0569] M-(1S,2S)-N-((6 3 S,4S,Z)-1 1 -Ethyl-1 4 -Fluorine-1 2 -((S)-8-((S)-1-methoxyethyl)-3-methyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-d]pyrido[2,3-b][1,4]oxazin-9-yl-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazo-1(5,3)-indolaz-6(1,3)-pyridazine-cycloundecafen-4-yl)-2-methylcyclopropane-1-carboxamide 5-p1

[0570] M-(1S,2S)-N-((6 3 S,4S,Z)-1 1 -Ethyl-1 4 -Fluorine-1 2 -((R)-8-((S)-1-methoxyethyl)-3-methyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-d]pyrido[2,3-b][1,4]oxazin-9-yl-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-11 H-8-oxa-2(4,2)-thiazo-1(5,3)-indolaz-6(1,3)-pyridazine-cycloundecafen-4-yl)-2-methylcyclopropane-1-carboxamide 5-p2

[0571] P-(1S,2S)-N-((6 3 S,4S,Z)-1 1 -Ethyl-1 4 -Fluorine-1 2 -((S)-8-((S)-1-methoxyethyl)-3-methyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-d]pyrido[2,3-b][1,4]oxazin-9-yl-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazo-1(5,3)-indolaz-6(1,3)-pyridazine-cycloundecafen-4-yl)-2-methylcyclopropane-1-carboxamide 5-p3

[0572] P-(1S,2S)-N-((6 3 S,4S,Z)-1 1 -Ethyl-1 4 -Fluorine-1 2 -((R)-8-((S)-1-methoxyethyl)-3-methyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-d]pyrido[2,3-b][1,4]oxazin-9-yl-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazo-1(5,3)-indolaz-6(1,3)-pyridazine-cycloundecafen-4-yl)-2-methylcyclopropane-1-carboxamide 5-p4

[0573] MS m / z(ESI): 857.4 [M+1].

[0574] Example 6

[0575] (1S,2S)-N-((6 3 S,4S,Z)-1 1 -Ethyl-14 -Fluorine-1 2 -(9-((S)-1-methoxyethyl)-3-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyridino[3,2-e][1,4]oxazopentane-10-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazo-1(5,3)-indolaz-6(1,3)-pyridazine-cycloundecaban-4-yl)-2-methylcyclopropane-1-carboxamide 6

[0576] M-(1S,2S)-N-((6 3 S,4S,Z)-1 1 -Ethyl-1 4 -Fluorine-1 2 -((S)-9-((S)-1-methoxyethyl)-3-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyridino[3,2-e][1,4]oxazopentane-10-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazo-1(5,3)-indolaz-6(1,3)-pyridazine-cycloundecafen-4-yl)-2-methylcyclopropane-1-carboxamide 6-p1

[0577] M-(1S,2S)-N-((6 3 S,4S,Z)-1 1 -Ethyl-1 4 -Fluorine-1 2 -((R)-9-((S)-1-methoxyethyl)-3-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyridino[3,2-e][1,4]oxazopentane-10-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1H-8-oxa-2(4,2)-thiazo-1(5,3)-indolaz-6(1,3)-pyridazine-cycloundecafen-4-yl)-2-methylcyclopropane-1-carboxamide 6-p2

[0578] P-(1S,2S)-N-((6 3 S,4S,Z)-1 1 -Ethyl-1 4 -Fluorine-1 2 -((S)-9-((S)-1-methoxyethyl)-3-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyridino[3,2-e][1,4]oxazopentane-10-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazo-1(5,3)-indolaz-6(1,3)-pyridazine-cycloundecaban-4-yl)-2-methylcyclopropane-1-carboxamide 6-p3

[0579] P-(1S,2S)-N-((6 3 S,4S,Z)-1 1 -Ethyl-1 4 -Fluorine-1 2 -((R)-9-((S)-1-methoxyethyl)-3-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyridino[3,2-e][1,4]oxazopentane-10-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazo-1(5,3)-indolaz-6(1,3)-pyridazine-cycloundecafen-4-yl)-2-methylcyclopropane-1-carboxamide 6-p4

[0580] MS m / z(ESI): 871.4 [M+1].

[0581] Example 7

[0582] (1S,2S)-N-((6 3 S,4S,Z)-1 1-Ethyl-1 6 -Fluorine-1 2 -(9-((S)-1-methoxyethyl)-3-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyridino[3,2-e][1,4]oxazopentane-10-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazo-1(5,3)-indolaz-6(1,3)-pyridazine-cycloundecaban-4-yl)-2-methylcyclopropane-1-carboxamide 7

[0583] M-(1S,2S)-N-((6 3 S,4S,Z)-1 1 -Ethyl-1 6 -Fluorine-1 2 -((S)-9-((S)-1-methoxyethyl)-3-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyridino[3,2-e][1,4]oxazopentane-10-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazo-1(5,3)-indolaz-6(1,3)-pyridazine-cycloundecafen-4-yl)-2-methylcyclopropane-1-carboxamide 7-p1

[0584] M-(1S,2S)-N-((6 3 S,4S,Z)-1 1 -Ethyl-1 6 -Fluorine-1 2 -((R)-9-((S)-1-methoxyethyl)-3-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyridino[3,2-e][1,4]oxazopentane-10-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-11 H-8-oxa-2(4,2)-thiazo-1(5,3)-indolaz-6(1,3)-pyridazine-cycloundecafen-4-yl)-2-methylcyclopropane-1-carboxamide 7-p2

[0585] P-(1S,2S)-N-((6 3 S,4S,Z)-1 1 -Ethyl-1 6 -Fluorine-1 2 -((S)-9-((S)-1-methoxyethyl)-3-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyridino[3,2-e][1,4]oxazopentane-10-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazo-1(5,3)-indolaz-6(1,3)-pyridazine-cycloundecafen-4-yl)-2-methylcyclopropane-1-carboxamide 7-p3

[0586] P-(1S,2S)-N-((6 3 S,4S,Z)-1 1 -Ethyl-1 6 -Fluorine-1 2 -((R)-9-((S)-1-methoxyethyl)-3-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyridino[3,2-e][1,4]oxazopentane-10-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazo-1(5,3)-indolaz-6(1,3)-pyridazine-cycloundecafen-4-yl)-2-methylcyclopropane-1-carboxamide 7-p4

[0587] MS m / z(ESI): 871.4 [M+1].

[0588] Example 8

[0589] (1r,2R,3S)-N-((6 3S,4S,Z)-1 1 -Ethyl-1 4 -Fluorine-1 2 -((S)-8-((S)-1-methoxyethyl)-3-methyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-d]pyrido[2,3-b][1,4]oxazin-9-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazo-1(5,3)-indolaz-6(1,3)-pyridazine-cycloundecaban-4-yl)-2,3-dimethylcyclopropane-1-carboxamide 8

[0590] M-(1r,2R,3S)-N-((6 3 S,4S,Z)-1 1 -Ethyl-1 4 -Fluorine-1 2 -((S)-8-((S)-1-methoxyethyl)-3-methyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-d]pyrido[2,3-b][1,4]oxazin-9-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazo-1(5,3)-indolaz-6(1,3)-pyridazine-cycloundecaban-4-yl)-2,3-dimethylcyclopropane-1-carboxamide 8-p1

[0591] P-(1r,2R,3S)-N-((6 3 S,4S,Z)-1 1 -Ethyl-1 4 -Fluorine-1 2 -((S)-8-((S)-1-methoxyethyl)-3-methyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-d]pyrido[2,3-b][1,4]oxazin-9-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6-hexahydro-1 1 H-8-oxa-2(4,2)-thiazo-1(5,3)-indolaz-6(1,3)-pyridazine-cycloundecaban-4-yl)-2,3-dimethylcyclopropane-1-carboxamide 8-p2

[0592] first step

[0593] (S)-8-((S)-1-methoxyethyl)-9-(4,4,5,5-tetramethyl-1,3,2-dioxoborhexacyclopentan-2-yl)-1,2,4a,5-tetrahydropyrazino[1,2-d]pyrido[2,3-b][1,4]oxazine-3(4H)-carboxylic acid benzyl ester 8b

[0594] Using steps seven through ten of the synthetic route in Example 1, the starting compound 4-benzyl-1-(tert-butyl)-2-(hydroxymethyl)piperazine-1,4-dicarboxylic acid ester from step seven was replaced with 4-benzyl-1-(tert-butyl)(S)-2-(hydroxymethyl)piperazine-1,4-dicarboxylic acid ester 8a (prepared using the method disclosed in Example 22B on page 114 of patent application “US2022348574”), to obtain title compound 8b (450 mg, yield: 36.4%).

[0595] MS m / z(ESI): 510.5 [M+1].

[0596] Step 2

[0597] 1-(5-bromo-4-fluoro-1H-indol-3-yl)-3-((tert-butyldiphenylsilyl)oxy)-2,2-dimethylprop-1-one 8d

[0598] 3-((tert-butyldiphenylsilyl)oxy)-2,2-dimethylpropionyl chloride (17.88 g, 47.68 mmol, prepared by the method disclosed in compound A4 on page 46 of patent application "WO2023025832") was dissolved in dichloromethane (100 mL), cooled to 0 °C, and tin tetrachloride (12.42 g, 47.67 mmol) was slowly added. The mixture was stirred for 30 minutes while maintaining the temperature. Then, 5-bromo-4-fluoro-1H-indole 8c (10.2 g, 47.67 mmol, Shanghai Bide) was added dropwise and the mixture was stirred for 10 minutes. The reaction solution was quenched with saturated sodium chloride aqueous solution, extracted with dichloromethane (100 mL × 3), the organic phases were combined, washed with saturated sodium bicarbonate, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to give the title compound 8d (15 g, yield: 57.2%).

[0599] MS m / z(ESI): 552.5 [M+1].

[0600] Step 3

[0601] 1-(5-bromo-4-fluoro-1H-indol-3-yl)-3-((tert-butyldiphenylsilyl)oxy)-2,2-dimethylprop-1-ol 8e

[0602] Compound 8d (15.08 g, 27.29 mmol) was dissolved in tetrahydrofuran (250 mL), and lithium borohydride (2.081 g, 95.53 mmol) was added. The mixture was heated to 60 °C and reacted for 12 hours. After the reaction solution cooled to room temperature, it was quenched with saturated sodium chloride solution and extracted with ethyl acetate (100 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title compound 8e (15.13 g). The product was used directly in the next reaction without purification.

[0603] MS m / z(ESI): 554.5 [M+1].

[0604] Step 4

[0605] 5-Bromo-3-(3-((tert-butyldiphenylsilyl)oxy)-2,2-dimethylpropyl)-4-fluoro-1H-indole 8f

[0606] The crude compound 8e (15.13 g, 27.29 mmol) was dissolved in dichloromethane (250 mL), and trifluoroacetic acid (12.448 g, 109.17 mmol) and triethylsilane (12.69 g, 109.17 mmol) were added. The mixture was stirred for 2 hours. The pH of the reaction solution was adjusted to >7 with saturated sodium bicarbonate solution, and the mixture was extracted with dichloromethane (100 mL × 2). The organic phases were combined, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to give the title compound 8f (11.57 g, yield: 78.8%).

[0607] MS m / z(ESI): 538.4 [M+1].

[0608] Step 5

[0609] 8g of 3-(5-bromo-4-fluoro-1H-indol-3-yl)-2,2-dimethylprop-1-ol

[0610] Compound 8f (18 g, 33.4 mmol) was dissolved in tetrahydrofuran (300 mL), and a 1 M tetrabutylammonium fluoride tetrahydrofuran solution (167.5 mL) was added. The mixture was heated to 50 °C and stirred for 12 hours. The reaction solution was concentrated under reduced pressure, and the residue was extracted with ethyl acetate (150 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using elution system B to give the title compound 8f (10.4 g, yield: 103%).

[0611] MS m / z(ESI): 300.2 [M+1].

[0612] Step 6

[0613] 3-(5-bromo-4-fluoro-1H-indol-3-yl)-2,2-dimethylpropyl acetate 8h

[0614] 8 g (10.5 g, 33.2 mmol) of compound was dissolved in dichloromethane (300 mL). Triethylamine (10.1 g, 99.7 mmol), acetic anhydride (3.4 g, 33.3 mmol), and 4-dimethylaminopyridine (410 mg, 3.32 mmol) were added under ice bath conditions. The mixture was stirred at the same temperature for 20 minutes. Water was added to the reaction solution, and the mixture was extracted with dichloromethane (100 mL × 3). The organic phases were combined to obtain crude compound 8 h (11.4 g). The product was used directly in the next reaction without purification.

[0615] MS m / z(ESI): 340.2 [M-1].

[0616] Step 7

[0617] 3-(4-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxoborhexacyclopentan-2-yl)-1H-indol-3-yl)-2,2-dimethylpropyl acetate 8i

[0618] Compound 8h (994 mg, 2.91 mmol), potassium acetate (713 mg, 7.26 mmol), pinacol diboronate (1.85 g, 7.27 mmol), and 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (213 mg, 291.1 μmol) were dissolved in toluene (40 mL). The mixture was heated to 100 °C and reacted for 12 hours under a nitrogen atmosphere. After the reaction solution was cooled to room temperature, it was filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using elution system B to give the title compound 8i (1 g, yield: 89.9%).

[0619] MS m / z(ESI): 390.5 [M+1].

[0620] Step 8

[0621] (S)-3-(4-(3-(3-acetoxy-2,2-dimethylpropyl)-4-fluoro-1H-indol-5-yl)thiazo-2-yl)-2-((tert-butoxycarbonyl)amino)methyl propionate 8j

[0622] Compound 8i (1.01 g, 2.61 mmol), methyl (S)-3-(4-bromothiazol-2-yl)-2-((tert-butoxycarbonyl)amino)propionate (1.05 g, 2.87 mmol, prepared by the method disclosed in Intermediate B on page 33 of patent application "WO2024017859"), 1,1'-bis(diphenylphosphine)ferrocene palladium(II) dichloride (383 mg, 523.4 μmol), and potassium phosphate (1.39 g, 6.53 mmol) were dissolved in toluene (30 mL), 1,4-dioxane (10 mL), and water (10 mL). The reaction was carried out under nitrogen atmosphere at 70 °C for 12 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to give title compound 8j (1.4 g, yield: 97.8%).

[0623] MS m / z(ESI): 548.5 [M+1].

[0624] Step 9

[0625] (S)-3-(4-(3-(3-acetoxy-2,2-dimethylpropyl)-4-fluoro-2-iodo-1H-indol-5-yl)thiazo-2-yl)-2-((tert-butoxycarbonyl)amino)methyl propionate 8k

[0626] Compound 8j (1.4 g, 2.55 mmol) was dissolved in tetrahydrofuran (50 mL), and silver trifluoromethanesulfonate (789 mg, 3.07 mmol, Shanghai Titan) and sodium bicarbonate (258 mg, 3.07 mmol) were added. The mixture was cooled to 0 °C, and a tetrahydrofuran solution of iodine (616 mg, 2.42 mmol) was added dropwise (5 mL). The mixture was then stirred at room temperature for 30 minutes. The reaction mixture was quenched with saturated sodium sulfite aqueous solution, and extracted with ethyl acetate (30 mL × 3). The organic phases were combined, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to give the title compound 8k (1.1 g, yield: 63.4%).

[0627] MS m / z(ESI): 674.4 [M+1].

[0628] Step 10

[0629] (S)-2-((tert-butoxycarbonyl)amino)-3-(4-(4-fluoro-3-(3-hydroxy-2,2-dimethylpropyl)-2-iodo-1H-indol-5-yl)thiazolyl-2-yl)propionic acid 8l

[0630] Compound 8k (1.1 g, 1.62 mmol) was dissolved in tetrahydrofuran (18 mL) and water (6 mL), and lithium hydroxide monohydrate (205 mg, 4.88 mmol) was added. The mixture was stirred for 16 hours. The pH of the reaction solution was adjusted to <7 with 1 M hydrochloric acid, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title compound 8l (1 g). The product was used directly in the next reaction without purification.

[0631] MS m / z(ESI): 618.5 [M+1].

[0632] Step 11

[0633] (1r,2R,3S)-N-((6 3 S,4S,Z)-1 1 -Ethyl-1 4 -Fluorine-1 2 -((S)-8-((S)-1-methoxyethyl)-3-methyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-d]pyrido[2,3-b][1,4]oxazin-9-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazo-1(5,3)-indolaz-6(1,3)-pyridazine-cycloundecaban-4-yl)-2,3-dimethylcyclopropane-1-carboxamide 8

[0634] M-(1r,2R,3S)-N-((6 3 S,4S,Z)-1 1 -Ethyl-1 4 -Fluorine-1 2 -((S)-8-((S)-1-methoxyethyl)-3-methyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-d]pyrido[2,3-b][1,4]oxazin-9-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 56 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazo-1(5,3)-indolaz-6(1,3)-pyridazine-cycloundecaban-4-yl)-2,3-dimethylcyclopropane-1-carboxamide 8-p1

[0635] P-(1r,2R,3S)-N-((6 3 S,4S,Z)-1 1 -Ethyl-1 4 -Fluorine-1 2 -((S)-8-((S)-1-methoxyethyl)-3-methyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-d]pyrido[2,3-b][1,4]oxazin-9-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazo-1(5,3)-indolaz-6(1,3)-pyridazine-cycloundecaban-4-yl)-2,3-dimethylcyclopropane-1-carboxamide 8-p2

[0636] Using the synthetic route in Example 1, the starting material 11 in step 11 was replaced with compound 81, the starting material 1k in step 14 was replaced with compound 8b, and the starting material (1S,2S)-2-methylcyclopropane-1-carboxylic acid in step 19 was replaced with compound (1r,2R,3S)-2,3-dimethylcyclopropane-1-carboxylic acid (Shanghai Bide) to obtain crude title compound 8 (40 mg). This was purified by preparative high-performance liquid chromatography (Waters-2545, column: Welch Xtimate C18, 30*250 mm, 5 μm; mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 55%-65%, flow rate: 30 mL / min) to obtain the title compound (3 mg, yield: 7.5%).

[0637] Single configuration compound (shorter retention time): (3 mg, yield: 7.5%).

[0638] MS m / z(ESI): 871.7 [M+1].

[0639] HPLC analysis: retention time 2.88 min, purity: 97% (column: Ultimate, C18, 1.8 μm, 2.1*50 mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%).

[0640] 1 H NMR (500MHz, CD3OD): δ7.44(s,1H),7.36–7.30(m,2H),7.18(s,1H),6.04(d,1H),4.60(s,2H),4.53(dd,1H),4.39(d,1H),4 .25(dd,1H),4.20–4.11(m,1H),4.03(d,2H),3.86(s,1H),3.75(d,2H),3.58(dd,2H),3.30–3.28(m,1H),3.10–2.97(m,5H), 2.90–2.81(m,2H),2.60–2.51(m,2H),2.40(s,2H),2.35–2.25(m,2H),2.21(t,1H),2.09–2.02(m,1H),1.94(t,1H),1.62(d, 1H),1.53(s,1H),1.43(d,3H),1.36(dt,4H),1.31(d,3H),1.13(d,3H),1.10(d,2H),1.05(t,1H),0.92(t,1H),0.73(s,3H).

[0641] Single-configuration compound (longer retention time): (3 mg, yield: 7.5%).

[0642] MS m / z(ESI): 871.7 [M+1].

[0643] HPLC analysis: retention time 3.94 min, purity: 99% (column: Ultimate, C18, 1.8 μm, 2.1*50 mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%).

[0644] 1H NMR (500MHz, DMSO-d6): δ8.27-8.25(m,1H),7.66(s,1H),7.40-7.34(m,3H),5.77-5.72(m,1H),4.88-4.85(m,1H),4.45-4.42( m,1H),4.29-4.26(m,1H),4.18-4.13(m,1H),3.97-3.89(m,2H),3.88-3.79(m,2H),3.51-3.48(m,1H),3.43-3.40(m,2H),3.28- 3.23(m,3H),3.20-3.16(m,1H),3.11-3.06(m,4H),2.87-2.85(m,2H),2.64-2.52(m,3H),2.24(s,3H),2.11-2.06(m,1H),2.01- 1.96(m,1H),1.76-1.70(m,2H),1.47-1.34(m,3H),1.29-1.21(m,4H),1.18-1.14(m,4H),1.08-1.01(m,8H),0.91-0.90(m,3H).

[0645] Example 9

[0646] (1r,2R,3S)-N-((6 3 S,4S,Z)-1 1 -Ethyl-1 4 -Fluorine-1 2 -((R)-8-((S)-1-methoxyethyl)-3-methyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-d]pyrido[2,3-b][1,4]oxazin-9-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazo-1(5,3)-indolaz-6(1,3)-pyridazine-cycloundecaban-4-yl)-2,3-dimethylcyclopropane-1-carboxamide 9

[0647] M-(1r,2R,3S)-N-((6 3 S,4S,Z)-1 1 -Ethyl-1 4 -Fluorine-1 2-((R)-8-((S)-1-methoxyethyl)-3-methyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-d]pyrido[2,3-b][1,4]oxazin-9-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazo-1(5,3)-indolaz-6(1,3)-pyridazine-cycloundecaban-4-yl)-2,3-dimethylcyclopropane-1-carboxamide 9-p1

[0648] P-(1r,2R,3S)-N-((6 3 S,4S,Z)-1 1 -Ethyl-1 4 -Fluorine-1 2 -((R)-8-((S)-1-methoxyethyl)-3-methyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-d]pyrido[2,3-b][1,4]oxazin-9-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazo-1(5,3)-indolaz-6(1,3)-pyridazine-cycloundecaban-4-yl)-2,3-dimethylcyclopropane-1-carboxamide 9-p2

[0649] Using the synthetic route in Example 8, the first-step starting compound 8a was replaced with compound 4-benzyl-1-(tert-butyl)(R)-2-(hydroxymethyl)piperazine-1,4-dicarboxylate (prepared by the method disclosed in 60-A on page 143 of patent application "WO2022150707") to obtain the title compound (5.4 mg, yield: 22.8%) and (3.1 mg, yield: 13.1%).

[0650] Single configuration compound (shorter retention time): (5.4 mg, yield: 22.8%).

[0651] MS m / z(ESI): 871.9 [M+1].

[0652] HPLC analysis: retention time 2.74 min, purity: 95% (column: Xtimate, C18, 1.8 μm, 2.1*50 mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%).

[0653] 1 H NMR (500MHz, DMSO-d6): δ8.26-8.24(m,1H),7.66(s,1H),7.39-7.33(m,2H),7.20(s,1H),6.66(s,1H),5.75-5.72(m,1H),5.36- 5.32(m,1H),4.87-4.85(m,1H),4.45-4.43(m,1H),4.29-4.27(m,1H),4.16-4.12(m,1H),4.01-3.88(m,3H),3.81-3.79(m,1H), 3.51-3.48(m,1H),3.43-3.37(m,2H),3.28-3.17(m,4H),3.15(s,3H),2.86-2.81(m,2H),2.74-2.69(m,1H),2.65-2.59(m,2H), 2.24-2.23(m,3H),2.08-1.98(m,4H),1.77-1.73(m,2H),1.46-1.34(m,3H),1.24(s,6H),1.16-1.08(m,6H),1.05-1.02(m,4H).

[0654] Single-configuration compound (longer retention time): (3.1 mg, yield: 13.1%).

[0655] MS m / z(ESI): 871.9 [M+1].

[0656] HPLC analysis: retention time 2.80 min, purity: 96% (column: Xtimate, C18, 1.8 μm, 2.1*50 mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%).

[0657] 1H NMR (500MHz, CD3OD): δ7.43-7.42(m,1H),7.37-7.31(m,2H),7.20(s,1H),6.04-6.02(m,1H),4.60(s,1H),4.54-4.51(m,1H),4.40 -4.38(m,1H),4.25-4.21(m,1H),4.15-4.10(m,1H),4.06-3.98(m,2H),3.86-3.74(m,3H),3.61-3.52(m,2H),3.29-3.26(m,2H),3 .07-2.93(m,6H),2.84-2.79(m,1H),2.60-2.53(m,1H),2.39(s,3H),2.32-2.27(m,1H),2.22-2.19(m,1H),2.05-2.04(m,1H),1.9 5-1.91(m,1H),1.66-1.58(m,1H),1.50-1.49(m,1H),1.41-1.40(m,3H),1.38-1.22(m,9H),1.17-1.04(m,6H),0.80-0.76(m,3H).

[0658] Example 10

[0659] (1r,2R,3S)-N-((6 3 S,4S,Z)-1 1 -Ethyl-1 6 -Fluorine-1 2 -(8-((S)-1-methoxyethyl)-3-methyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-d]pyridino[2,3-b][1,4]oxazin-9-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazo-1(5,3)-indolaz-6(1,3)-pyridazine-cycloundecafen-4-yl)-2,3-dimethylcyclopropane-1-carboxamide 10

[0660] P-(1r,2R,3S)-N-((6 3 S,4S,Z)-1 1 -Ethyl-1 6 -Fluorine-1 2-((R)-8-((S)-1-methoxyethyl)-3-methyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-d]pyrido[2,3-b][1,4]oxazin-9-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazo-1(5,3)-indolaz-6(1,3)-pyridazine-cycloundecafen-4-yl)-2,3-dimethylcyclopropane-1-formamide 10-p1

[0661] M-(1r,2R,3S)-N-((6 3 S,4S,Z)-1 1 -Ethyl-1 6 -Fluorine-1 2 -((S)-8-((S)-1-methoxyethyl)-3-methyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-d]pyrido[2,3-b][1,4]oxazin-9-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazo-1(5,3)-indolaz-6(1,3)-pyridazine-cycloundecaban-4-yl)-2,3-dimethylcyclopropane-1-carboxamide 10-p2

[0662] M-(1r,2R,3S)-N-((6 3 S,4S,Z)-1 1 -Ethyl-1 6 -Fluorine-1 2 -((R)-8-((S)-1-methoxyethyl)-3-methyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-d]pyrido[2,3-b][1,4]oxazin-9-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1H-8-oxa-2(4,2)-thiazo-1(5,3)-indolaz-6(1,3)-pyridazine-cycloundecaban-4-yl)-2,3-dimethylcyclopropane-1-carboxamide 10-p3

[0663] P-(1r,2R,3S)-N-((6 3 S,4S,Z)-1 1 -Ethyl-1 6 -Fluorine-1 2 -((S)-8-((S)-1-methoxyethyl)-3-methyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-d]pyrido[2,3-b][1,4]oxazin-9-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazo-1(5,3)-indolaz-6(1,3)-pyridazine-cycloundecafen-4-yl)-2,3-dimethylcyclopropane-1-carboxamide 10-p4

[0664] Using the synthetic route in Example 8, the first-step starting compound 8a was replaced with 4-benzyl-1-(tert-butyl)-2-(hydroxymethyl)piperazine-1,4-dicarboxylic acid ester, and the fifth-step starting compound 8f was replaced with 5-bromo-3-(3-((tert-butyldiphenylsilyl)oxy)-2,2-dimethylpropyl)-6-fluoro-1H-indole (prepared using the method disclosed in Intermediate C on page 37 of patent application "WO2024017859"), to obtain crude title compound 10 (150 mg). Purification was performed by preparative high-performance liquid chromatography (Waters-2545, column: Welch Xtimate C18, 30*250mm, 5μm; mobile phase: aqueous phase (10mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 55%-65%, flow rate: 30mL / min) to give the title compound (20mg, yield: 13.3%), (10mg, yield: 6.6%), (10mg, yield: 6.6%), and (20mg, yield: 13.3%).

[0665] Single-configuration compound (shortest retention time): (20 mg, yield: 13.3%).

[0666] MS m / z(ESI): 871.9 [M+1].

[0667] HPLC analysis: retention time 3.04 min, purity: 98% (column: Ultimate, C18, 1.8 μm, 2.1*50 mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%).

[0668] 1 H NMR (500MHz, CD3OD): δ8.63(d,1H),7.66(d,1H),7.29(d,1H),7.25(s,1H),5.67(dd,1H),4.82(d,1H),4.53(dd,1H),4.4 6(d,1H),4.26(dt,2H),4.04(dq,1H),3.96(q,1H),3.86–3.75(m,2H),3.72(t,2H),3.51–3.45(m,1H),3.30-3.27(m,1H) ,3.24(s,2H),3.15(d,1H),3.01-2.93(m,2H),2.83(dtd,2H),2.48(d,1H),2.40(s,2H),2.32–2.19(m,2H),2.09–2.02(m ,1H),1.95(q,2H),1.90–1.80(m,1H),1.72–1.57(m,2H),1.48–1.25(m,8H),1.23–1.13(m,7H),1.03(s,3H),0.63(s,3H).

[0669] Single configuration compound (shorter retention time): (10 mg, yield: 6.6%).

[0670] MS m / z(ESI): 871.9 [M+1].

[0671] HPLC analysis: retention time 3.09 min, purity: 94% (column: Ultimate, C18, 1.8 μm, 2.1*50 mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%).

[0672] 1H NMR (500MHz, CD3OD): δ8.63(d,1H),7.65(d,1H),7.30(d,1H),7.13(s,1H),5.79(d,1H),4.60(s,2H),4.52 (dd,1H),4.46(d,1H),4.26(dd,1H),4.22–4.13(m,3H),3.82–3.69(m,3H),3.49–3.43(m,2H),3.29(s,3H), 3.01(t,3H),2.80(q,2H),2.63(d,1H),2.39(s,2H),2.31(t,1H),2.20(q,2H),2.05(d,1H),2.00–1.89(m,2 H),1.79(d,2H),1.64(d,3H),1.40(d,3H),1.21–1.13(m,5H),1.03(t,2H),0.98–0.89(m,4H),0.58(s,3H).

[0673] Single-configuration compound (longer retention time): (10 mg, yield: 6.6%).

[0674] MS m / z(ESI): 871.9 [M+1].

[0675] HPLC analysis: retention time 3.12 min, purity: 99% (column: Ultimate, C18, 1.8 μm, 2.1*50 mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%).

[0676] 1 H NMR (500MHz, CD3OD): δ8.64(d,1H),7.65(d,1H),7.30(d,1H),7.17(s,1H),5.79(d,1H),4.52(dd,1H),4.4 6(d,1H),4.27–4.12(m,5H),3.79(d,2H),3.71(d,1H),3.44(s,1H),3.30(s,3H),3.01(dd,3H),2.83(dtd,3 H),2.68(d,1H),2.40(s,2H),2.29(td,2H),2.24–2.16(m,2H),2.05(d,1H),2.00–1.90(m,2H),1.80(d,1H ),1.70–1.59(m,2H),1.45–1.40(m,1H),1.37(d,3H),1.16(dd,6H),1.02(t,3H),0.96(s,3H),0.57(s,3H).

[0677] Single-configuration compound (longest retention time): (20 mg, yield: 13.3%).

[0678] MS m / z(ESI): 871.9 [M+1].

[0679] HPLC analysis: retention time 3.18 min, purity: 99% (column: Ultimate, C18, 1.8 μm, 2.1*50 mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%).

[0680] 1 H NMR (500MHz, CD3OD): δ8.63(d,1H),7.66(d,1H),7.32–7.24(m,2H),5.67(d,1H),4.53(dd,1H),4.46(d,1H),4.31–4.20(m,2H),4 .02(dq,1H),3.93(q,1H),3.85–3.74(m,3H),3.71(d,1H),3.51–3.45(m,1H),3.29(d,1H),3.21(s,2H),3.15(d,1H),3.05–2.96( m,2H),2.85–2.72(m,2H),2.48–2.41(m,1H),2.40(s,2H),2.35–2.18(m,3H),2.05(d,1H),2.01–1.89(m,2H),1.88–1.81(m,1H), 1.70–1.59(m,2H),1.47–1.34(m,4H),1.29–1.23(m,4H),1.22–1.18(m,3H),1.16(d,3H),1.03(s,3H),0.92(t,1H),0.68(s,3H).

[0681] Example 11

[0682] (1r,2R,3S)-N-((6 3 S,4S,Z)-1 2 -(S)-3-(3-Cyclopropylprop-2-yn-1-yl)-8-((S)-1-methoxyethyl)-1,2,3,4,4a,5-hexahydropyrazino[1,2-d]pyrido[2,3-b][1,4]oxazin-9-yl)-1 1 -Ethyl-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6-hexahydro-1 1 H-8-oxa-2(4,2)-thiazo-1(5,3)-indolaz-6(1,3)-pyridazine-cycloundecaban-4-yl)-2,3-dimethylcyclopropane-1-formamide 11

[0683] M-(1r,2R,3S)-N-((6 3 S,4S,Z)-1 2 -(S)-3-(3-Cyclopropylprop-2-yn-1-yl)-8-((S)-1-methoxyethyl)-1,2,3,4,4a,5-hexahydropyrazino[1,2-d]pyrido[2,3-b][1,4]oxazin-9-yl)-1 1 -Ethyl-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazo-1(5,3)-indolaz-6(1,3)-pyridazine-cycloundecaban-4-yl)-2,3-dimethylcyclopropane-1-carboxamide 11-p1

[0684] P-(1r,2R,3S)-N-((6 3 S,4S,Z)-1 2 -(S)-3-(3-Cyclopropylprop-2-yn-1-yl)-8-((S)-1-methoxyethyl)-1,2,3,4,4a,5-hexahydropyrazino[1,2-d]pyrido[2,3-b][1,4]oxazin-9-yl)-1 1 -Ethyl-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazo-1(5,3)-indolaz-6(1,3)-pyridazine-cycloundecaban-4-yl)-2,3-dimethylcyclopropane-1-carboxamide 11-p2

[0685] first step

[0686] ((6 3 S,4S,Z)-1 1 -Ethyl-1 2-((S)-8-((S)-1-methoxyethyl)-1,2,3,4,4a,5-hexahydropyrazino[1,2-d]pyridino[2,3-b][1,4]oxazin-9-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazo-1(5,3)-indolaz-6(1,3)-pyridazine-cycloundecaban-4-yl) tert-butyl carbamate

[0687] Using the synthetic route in Example 1, the starting compound 1k in step fourteen was replaced with compound 8b to obtain title compound 11a (49 mg, yield: 70%).

[0688] MS m / z(ESI): 843.5 [M+1].

[0689] Step 2

[0690] ((6 3 S,4S,Z)-1 2 -((S)-3-(3-cyclopropylprop-2-yn-1-yl)-8-((S)-1-methoxyethyl)-1,2,3,4,4a,5-hexahydropyrazino[1,2-d]pyrido[2,3-b][1,4]oxazin-9-yl)-1 1 -Ethyl-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazo-1(5,3)-indolaz-6(1,3)-pyridazine-cycloundecaban-4-yl) tert-butyl carbamate 11b

[0691] Compound 11a (49 mg, 58.1 μmol) was dissolved in N,N-dimethylformamide (2 mL), and potassium carbonate (40 mg, 290.6 μmol) and (3-bromo-1-propyn-1-yl)cyclopropane (9 mg, 58.1 μmol) were added. The mixture was stirred for 12 hours, and the reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to give title compound 11b (14 mg, yield: 26.1%).

[0692] MS m / z(ESI): 921.9 [M+1].

[0693] Step 3

[0694] (1r,2R,3S)-N-((6 3 S,4S,Z)-1 2 -(S)-3-(3-Cyclopropylprop-2-yn-1-yl)-8-((S)-1-methoxyethyl)-1,2,3,4,4a,5-hexahydropyrazino[1,2-d]pyrido[2,3-b][1,4]oxazin-9-yl)-1 1 -Ethyl-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazo-1(5,3)-indolaz-6(1,3)-pyridazine-cycloundecaban-4-yl)-2,3-dimethylcyclopropane-1-formamide 11

[0695] M-(1r,2R,3S)-N-((6 3 S,4S,Z)-1 2 -(S)-3-(3-Cyclopropylprop-2-yn-1-yl)-8-((S)-1-methoxyethyl)-1,2,3,4,4a,5-hexahydropyrazino[1,2-d]pyrido[2,3-b][1,4]oxazin-9-yl)-1 1 -Ethyl-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazo-1(5,3)-indolaz-6(1,3)-pyridazine-cycloundecaban-4-yl)-2,3-dimethylcyclopropane-1-carboxamide 11-p1

[0696] P-(1r,2R,3S)-N-((6 3 S,4S,Z)-1 2 -(S)-3-(3-Cyclopropylprop-2-yn-1-yl)-8-((S)-1-methoxyethyl)-1,2,3,4,4a,5-hexahydropyrazino[1,2-d]pyrido[2,3-b][1,4]oxazin-9-yl)-1 1 -Ethyl-10,10-dimethyl-5,7-dioxo-6 1 62 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazo-1(5,3)-indolaz-6(1,3)-pyridazine-cycloundecaban-4-yl)-2,3-dimethylcyclopropane-1-carboxamide 11-p2

[0697] Using the synthetic route in Example 1, the starting compound 1t in step 18 was replaced with compound 11b, and the starting compound (1S,2S)-2-methylcyclopropane-1-carboxylic acid in step 19 was replaced with (1r,2R,3S)-2,3-dimethylcyclopropane-1-carboxylic acid, yielding crude title compound 11 (13 mg). Purification was performed by preparative high-performance liquid chromatography (Waters-2545, column: Welch Xtimate C18, 30*250 mm, 5 μm; mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 55%-65%, flow rate: 30 mL / min), yielding the title compound (1.5 mg, yield: 11.5%) and (1.6 mg, yield: 12.3%).

[0698] Single configuration compound (shorter retention time): (1.5 mg, yield: 11.5%).

[0699] MS m / z(ESI): 918.0 [M+1].

[0700] HPLC analysis: retention time 1.80 min, purity: 99% (column: Ultimate, C18, 1.8 μm, 2.1*50 mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%).

[0701] 1H NMR (500MHz, CD3OD): δ8.55(d,1H),7.69(dd,1H),7.55(s,1H),7.47(d,1H),7.14(s,1H),5.79(d,1H) ,5.36(dd,2H),4.60(s,4H),4.59–4.52(m,1H),4.32–4.15(m,3H),3.86–3.71(m,3H),3.52–3.42(m,2 H),3.05(dd,3H),2.80(t,2H),2.62(d,1H),2.49(dt,2H),2.22(q,6H),2.05(q,5H),1.75–1.59(m,4H ),1.41(d,2H),1.16(dd,5H),1.04(d,3H),0.99(s,3H),0.88–0.75(m,2H),0.62(dd,2H),0.56(s,3H).

[0702] Single-configuration compound (longer retention time): (1.6 mg, yield: 12.3%).

[0703] MS m / z(ESI): 918.0 [M+1].

[0704] HPLC analysis: retention time 1.84 min, purity: 99% (column: Ultimate, C18, 1.8 μm, 2.1*50 mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%).

[0705] 1H NMR (500MHz, CD3OD): δ8.56(d,1H),7.69(dd,1H),7.56(s,1H),7.45(d,1H),7.27(s,1H),5.68(d,1H),5.36(dd,2H),4.60(s,1H),4.54(dd ,1H),4.46(d,1H),4.37–4.22(m,2H),4.07(dd,1H),3.94(q,1H),3.89–3.68(m,4H),3.55–3.41(m,1H),3.21(s,3H),3.20–3.10(m,1H),3. 02(d,2H),2.85–2.71(m,2H),2.55–2.35(m,2H),2.34–2.24(m,1H),2 .24–2.17(m,2H),2.12(t,1H),2.05(q,2H),1.98(d,1H),1.89–1.81( m,1H),1.64(d,4H),1.23(d,3H),1.20(s,3H),1.16(d,3H),1.04(s,3H),0.97–0.88(m,4H),0.79(dd,2H),0.69(s,2H),0.64–0.55(m,2H).

[0706] Example 12

[0707] (1r,2R,3S)-N-((6 4 S,4S,Z)-1 1 -Ethyl-1 2 -((S)-8-((S)-1-methoxyethyl)-3-methyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-d]pyrido[2,3-b][1,4]oxazin-9-yl)-10,10-dimethyl-5,7-dioxo-1 1 H-8-Oza-6 2 6 3 -diaza-2(4,2)-thiazo-1(5,3)-indolaza-6(2,4)-bicyclo[3.1.1]heptaneheptan-1 / 2-heptan-4-yl)-2,3-dimethylcyclopropane-1-carboxamide 12

[0708] M-(1r,2R,3S)-N-((6 4 S,4S,Z)-1 1 -Ethyl-1 2 -((S)-8-((S)-1-methoxyethyl)-3-methyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-d]pyrido[2,3-b][1,4]oxazin-9-yl)-10,10-dimethyl-5,7-dioxo-11 H-8-Oza-6 2 6 3 -diaza-2(4,2)-thiazo-1(5,3)-indolaza-6(2,4)-bicyclo[3.1.1]heptaneheptan-1 / 2-heptan-4-yl)-2,3-dimethylcyclopropane-1-carboxamide 12-p1

[0709] P-(1r,2R,3S)-N-((6 4 S,4S,Z)-1 1 -Ethyl-1 2 -((S)-8-((S)-1-methoxyethyl)-3-methyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-d]pyrido[2,3-b][1,4]oxazin-9-yl)-10,10-dimethyl-5,7-dioxo-1 1 H-8-Oza-6 2 6 3 -diaza-2(4,2)-thiazo-1(5,3)-indolaza-6(2,4)-bicyclo[3.1.1]heptaneheptacyclohexane-4-yl)-2,3-dimethylcyclopropane-1-carboxamide 12-p2

[0710] Using the synthetic route in Example 1, the starting material 4-benzyl-1-(tert-butyl)-2-(hydroxymethyl)piperazine-1,4-dicarboxylic acid ester in step 7 was replaced with compound 8a; the starting material 1m in step 11 was replaced with (S)-2,3-diazabicyclo[3.1.1]heptane-4-carboxylic acid methyl ester bis(2,2,2-trifluoroacetate) 12a (prepared by the method disclosed in Reference Example 8 on page 64 of the specification in patent application "WO2024067857"); and the starting material (1S,2S)-2-methylcyclopropane-1-carboxylic acid in step 19 was replaced with compound (1r,2R,3S)-2,3-dimethylcyclopropane-1-carboxylic acid (Shanghai Bide) to obtain crude title compound 12 (47 mg). Purification was performed by preparative high-performance liquid chromatography (Waters-2545, column: Welch Xtimate C18, 30*150mm, 5μm; mobile phase: aqueous phase (10mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 35%-60%, flow rate: 30mL / min) to give the title compound (1.7mg, yield: 3.6%) and (2.7mg, yield: 5.7%).

[0711] Single configuration compound (shorter retention time): (1.7 mg, yield: 3.6%).

[0712] MS m / z(ESI): 865.9 [M+1].

[0713] HPLC analysis: retention time 1.56 min, purity: 97% (column: Ultimate, C18, 1.8 μm, 2.1*50 mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%).

[0714] 1 H NMR (500MHz, CD3OD): δ8.45-8.44(m,1H),7.69-7.67(m,1H),7.56(s,1H),7.49-7.47(m,1H),7.14(s,1H),4.68-4.65(m,1H),4.54-4.50( m,1H),4.27-4.22(m,2H),4.21-4.17(m,1H),3.76-3.71(m,2H),3.67-3.65(m,1H),3.45-3.41(m,1H),3.30-3.25(m,3H),3.00-2.98(m,2H ),2.81-2.76(m,1H),2.71-2.70(m,1H),2.65-2.57(m,3H),2.48-2.44(m,1H),2.39(s,3H),2.33-2.29(m,1H),2.25-2.17(m,3H),2.07-2. 03(m,3H),1.96-1.92(m,2H),1.63-1.61(m,3H),1.42-1.34(m,6H),1 .19-1.14(m,4H),1.05-1.02(m,2H),0.94-0.92(m,3H),0.56(s,3H).

[0715] Single-configuration compound (longer retention time): (2.7 mg, yield: 5.7%).

[0716] MS m / z(ESI): 865.9 [M+1].

[0717] HPLC analysis: Retention time 1.61 min, purity: 99% (Column: ACQUITY) C18, 1.7μm, 2.1*50mm; Mobile phase: water (10mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%).

[0718] 1H NMR (500MHz, CD3OD): δ8.44-8.43(m,1H),7.69-7.67(m,1H),7.56(s,1H),7.47-7. 45(m,1H),7.28(s,1H),5.92-5.90(m,1H),5.45-5.44(m,1H),4.78-4.76(m,1H),4 .69-4.66(m,1H),4.54-4.51(m,1H),4.25-4.21(m,1H),4.10-4.03(m,1H),3.95-3 .91(m,1H),3.86-3.80(m,1H),3.78-3.76(m,1H),3.73-3.65(m,2H),3.43-3.39(m, 2H),3.30-3.25(m,2H),3.24-3.21(m,3H),3.19-3.16(m,1H),3.00-2.98(m,2H),2 .80-2.73(m,2H),2.67-2.62(m,1H),2.51-2.45(m,2H),2.39(s,3H),2.33-2.27(m ,1H),2.23-2.19(m,1H),2.05-2.03(m,1H),1.95-1.90(m,1H),1.72-1.69(m,1H), 1.50-1.45(m,1H),1.29-1.26(m,3H),1.23-1.15(m,8H),1.02(s,3H),0.67(s,3H).

[0719] Example 13

[0720] (1r,2R,3S)-N-((4'S,Z)-1'-ethyl-2'-((S)-8-((S)-1-methoxyethyl)-3-methyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-d]pyrido[2,3-b][1,4]oxazin-9-yl)-10',10'-dimethyl-5',7'-dioxospiro[cyclopropane-1,3'-8-oxa-2(4,2)-thiazo-1(5,3-indola-6(1,3-pyridazin-cycloundevanadium]-4'-yl)-2,3-dimethylcyclopropane-1-carboxamide 13

[0721] M-(1r,2R,3S)-N-((4'S,Z)-1'-ethyl-2'-((S)-8-((S)-1-methoxyethyl)-3-methyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-d]pyrido[2,3-b][1,4]oxazin-9-yl)-10',10'-dimethyl-5',7'-dioxospiro[cyclopropane-1,3'-8-oxa-2(4,2)-thiazo-1(5,3-indola-6(1,3-pyridazin-cycloundecan]-4'-yl)-2,3-dimethylcyclopropane-1-carboxamide 13-p1

[0722] P-(1r,2R,3S)-N-((4'S,Z)-1'-ethyl-2'-((S)-8-((S)-1-methoxyethyl)-3-methyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-d]pyrido[2,3-b][1,4]oxazin-9-yl)-10',10'-dimethyl-5',7'-dioxospiro[cyclopropane-1,3'-8-oxa-2(4,2)-thiazo-1(5,3-indola-6(1,3-pyridazin-cycloundecan]-4'-yl)-2,3-dimethylcyclopropane-1-carboxamide 13-p2

[0723] first step

[0724] 2-(1-(4-bromothiazol-2-yl)cyclopropyl)-2-((tert-butoxycarbonyl)amino)acetic acid 13b

[0725] 2-Amino-2-(1-(4-bromothiazol-2-yl)cyclopropyl)acetic acid 13a (2.4 g, 8.66 mmol, prepared by the method disclosed in Reference Example 10 on page 67 of patent application "WO2024067857") was dissolved in tetrahydrofuran (25 mL) and water (10 mL). Sodium bicarbonate (2.5 g, 29.76 mmol) and di-tert-butyl dicarbonate (2.27 g, 10.40 mmol) were added, and the mixture was stirred for 12 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain crude title compound 13b (2.6 g). The product was used directly in the next reaction without purification.

[0726] MS m / z(ESI): 377.3 [M+1].

[0727] Step 2

[0728] 2-(1-(4-bromothiazol-2-yl)cyclopropyl)-2-((tert-butoxycarbonyl)amino)methyl acetate 13c

[0729] The crude title compound 13b (2.5 g, 6.62 mmol) was dissolved in tetrahydrofuran (15 mL) and methanol (15 mL), and a 2 M trimethylsilyldiazomethane solution in n-hexane (6.7 mL) was added. The mixture was stirred for 12 hours, and the reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to give title compound 13c (840 mg, yield: 32.4%).

[0730] MS m / z(ESI): 391.3 [M+1].

[0731] Step 3

[0732] 2-(1-(4-(3-(3-acetoxy-2,2-dimethylpropyl)-1H-indol-5-yl)thiazolyl-2-yl)cyclopropyl)-2-((tert-butoxycarbonyl)amino)methyl acetate 13e

[0733] Compound 13c (740 mg, 1.89 mmol), 2,2-dimethyl-3-(5-(4,4,5,5-tetramethyl-1,3,2-dioxoborhexacyclopentan-2-yl)-1H-indol-3-yl)propyl acetate 13d (878 mg, 2.26 mmol, prepared by the method disclosed in Example 9 on page 81 of patent application "WO2024067857"), 1,1'-bis(diphenylphosphine)ferrocene palladium(II) dichloride (138 mg, 188 μmol), and potassium phosphate (1 g, 4.73 mmol) were dissolved in toluene (30 mL), 1,4-dioxane (10 mL), and water (10 mL). The reaction was carried out at 70 °C for 12 hours under a nitrogen atmosphere. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to give title compound 13e (800 mg, yield: 76.2%).

[0734] MS m / z(ESI): 556.6 [M+1].

[0735] Step 4

[0736] 2-(1-(4-(3-(3-acetoxy-2,2-dimethylpropyl)-2-iodo-1H-indol-5-yl)thiazolyl-2-yl)cyclopropyl)-2-((tert-butoxycarbonyl)amino)methyl acetate 13f

[0737] Compound 13e (400 mg, 720 μmol) was dissolved in tetrahydrofuran (15 mL), and silver trifluoromethanesulfonate (224 mg, 872 μmol) and sodium bicarbonate (74 mg, 880 μmol) were added. The mixture was cooled to 0 °C, and a tetrahydrofuran solution of iodine (179 mg, 705 μmol) (5 mL) was added dropwise. The mixture was then stirred at room temperature for 1 hour. The reaction mixture was quenched with saturated sodium sulfite aqueous solution, extracted with ethyl acetate (20 mL × 3), and the organic phases were combined and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to give the title compound 13f (412 mg, yield: 84%). MS m / z (ESI): 682.5 [M+1].

[0738] Step 5

[0739] 13g of 2-((tert-butoxycarbonyl)amino)-2-(1-(4-(3-(3-hydroxy-2,2-dimethylpropyl)-2-iodo-1H-indol-5-yl)thiazolyl)cyclopropyl)acetic acid

[0740] Compound 13f (412 mg, 604 μmol) was dissolved in tetrahydrofuran (10 mL) and water (3 mL), and lithium hydroxide monohydrate (76 mg, 1.81 mmol) was added. The mixture was stirred for 16 hours. The pH of the reaction solution was adjusted to <7 with 1 M hydrochloric acid, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain crude compound 13f (370 mg). The product was used directly in the next reaction without purification.

[0741] MS m / z(ESI): 626.5 [M+1].

[0742] Step 6

[0743] (1r,2R,3S)-N-((4'S,Z)-1'-ethyl-2'-((S)-8-((S)-1-methoxyethyl)-3-methyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-d]pyrido[2,3-b][1,4]oxazin-9-yl)-10',10'-dimethyl-5',7'-dioxospiro[cyclopropane-1,3'-8-oxa-2(4,2)-thiazo-1(5,3-indola-6(1,3-pyridazin-cycloundevanadium]-4'-yl)-2,3-dimethylcyclopropane-1-carboxamide 13

[0744] M-(1r,2R,3S)-N-((4'S,Z)-1'-ethyl-2'-((S)-8-((S)-1-methoxyethyl)-3-methyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-d]pyrido[2,3-b][1,4]oxazin-9-yl)-10',10'-dimethyl-5',7'-dioxospiro[cyclopropane-1,3'-8-oxa-2(4,2)-thiazo-1(5,3-indola-6(1,3-pyridazin-cycloundecan]-4'-yl)-2,3-dimethylcyclopropane-1-carboxamide 13-p1

[0745] P-(1r,2R,3S)-N-((4'S,Z)-1'-ethyl-2'-((S)-8-((S)-1-methoxyethyl)-3-methyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-d]pyrido[2,3-b][1,4]oxazin-9-yl)-10',10'-dimethyl-5',7'-dioxospiro[cyclopropane-1,3'-8-oxa-2(4,2)-thiazo-1(5,3-indola-6(1,3-pyridazin-cycloundecan]-4'-yl)-2,3-dimethylcyclopropane-1-carboxamide 13-p2

[0746] Using the synthetic route in Example 8, the starting material 8l in step eleven was replaced with compound 13g to obtain crude title compound 13 (28mg). Purification was performed by preparative high-performance liquid chromatography (Waters-2545, column: Welch Xtimate C18, 30×250mm, 5μm; mobile phase: aqueous phase (10mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 40%-65%, flow rate: 30mL / min) to obtain the title compound (3mg, yield: 10.7%) and (4mg, yield: 14.2%).

[0747] Single configuration compound (shorter retention time): (3 mg, yield: 10.7%).

[0748] MS m / z(ESI):880.0[M+1].

[0749] HPLC analysis: retention time 1.66 min, purity: 98% (column: Xtimate, C18, 1.8 μm, 2.1*50 mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%).

[0750] 1H NMR (500MHz, CD3OD): δ8.55(d,1H),7.65(dd,1H),7.45-7.42(m,2H),7.15(s,1H),5.36-5.33(m,1H),4. 52-4.46(m,2H),4.26-4.07(m,5H),3.78-3.72(m,2H),3.60(d,1H),3.17-3.15(m,3H),2.99-2.97(m,2H ),2.84-2.77(m,4H),2.38(s,3H),2.31-2.26(m,1H),2.21-2.16(m,2H),2.05-2.01(m,2H),1.97-1.89( m,2H),1.82-1.74(m,2H),1.68-1.59(m,2H),1.41-1.38(m,4H),1.34-1.25(m,10H),1.16-1.07(m,7H).

[0751] Single-configuration compound (longer retention time): (4 mg, yield: 14.2%).

[0752] MS m / z(ESI):880.0[M+1].

[0753] HPLC analysis: retention time 1.77 min, purity: 99% (column: Xtimate, C18, 1.8 μm, 2.1*50 mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%).

[0754] 1 H NMR (500MHz, CD3OD): δ8.50(d,1H),7.65(dd,1H),7.50(s,1H),7.41(d,1H),7.24(s,1H),6.22(s,1H),5.3 5-5.33(m,1H),4.75(d,1H),4.58-4.39(m,4H),4.24-4.20(m,1H),4.06-4.02(m,1H),3.91(q,1H),3.82-3 .70(m,4H),3.20(s,2H),3.14(d,1H),2.99-2.97(m,2H),2.83-2.72(m,2H),2.42(d,1H),2.37(s,2H),2.3 2-2.26(m,2H),2.05-1.74(m,5H),1.67-1.59(m,2H),1.42-1.11(m,17H),1.03-0.97(m,3H),0.66(s,2H).

[0755] Example 14

[0756] (1r,2R,3S)-N-((6 3 S,4S,Z)-1 1 -Ethyl-1 2 -((S)-9-((S)-1-methoxyethyl)-3-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyridino[3,2-e][1,4]oxazopentane-10-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazo-1(5,3)-indolaz-6(1,3)-pyridazine-cycloundecaban-4-yl)-2,3-dimethylcyclopropane-1-carboxamide 14M-(1r,2R,3S)-N-((6 3 S,4S,Z)-1 1 -Ethyl-1 2 -((S)-9-((S)-1-methoxyethyl)-3-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyridino[3,2-e][1,4]oxazopentane-10-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazo-1(5,3)-indolaz-6(1,3)-pyridazine-cycloundecaban-4-yl)-2,3-dimethylcyclopropane-1-carboxamide 14-p1

[0757] P-(1r,2R,3S)-N-((6 3 S,4S,Z)-1 1 -Ethyl-1 2 -((S)-9-((S)-1-methoxyethyl)-3-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyridino[3,2-e][1,4]oxazopentane-10-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 66 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazo-1(5,3)-indolaz-6(1,3)-pyridazine-cycloundecafen-4-yl)-2,3-dimethylcyclopropane-1-carboxamide 14-p2

[0758] first step

[0759] 5-Bromo-3-fluoro-2-(methoxycarbonyl)pyridine 1-oxide 14b

[0760] Methyl 5-bromo-3-fluoropyridinecarboxylate 14a (5.0 g, 21.36 mmol, Shanghai Biotech) was dissolved in dichloromethane (250 mL), cooled to 0 °C, and then trifluoroacetic anhydride (8.98 g, 42.73 mmol) and urea peroxide (4.02 g, 42.73 mmol, Sinopharm) were added. The mixture was allowed to return to room temperature naturally and stirred for 17 hours. Saturated sodium bicarbonate solution (100 mL) and saturated sodium sulfite solution (50 mL) were added to the reaction mixture, and the mixture was stirred for 30 minutes. The mixture was extracted with ethyl acetate (100 mL × 2), and the organic phases were combined. The mixture was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title compound 14b (5.3 g). The product was used directly in the next reaction without purification.

[0761] MS(ESI):250.0[M+H].

[0762] Step 2

[0763] methyl 5-bromo-6-cyano-3-fluoropyridinecarboxylate 14c

[0764] The crude compound 14b (4.7 g, 18.80 mmol), trimethylcyanosylsilane (18.65 g, 187.98 mmol), and N,N-dimethylformyl chloride (20.22 g, 187.98 mmol) were mixed and stirred at 60 °C for 48 hours. After the reaction solution cooled to room temperature, it was poured into a saturated sodium bicarbonate solution (50 mL) and extracted with ethyl acetate (50 mL × 2). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system B to give the title compound 14c (2.5 g, yield 51.3%).

[0765] Step 3: (S)-10-bromo-9-cyano-7-oxo-1,2,4a,5-tetrahydro-7H-pyrazino[2,1-c]pyridino[3,2-e][1,4]oxazepane-3(4H)-carboxylic acid tert-butyl ester 14d

[0766] Compound 14c (2.5 g, 9.65 mmol) was dissolved in acetonitrile (100 mL), and tert-butyl (3S)-3-(hydroxymethyl)piperazine-1-carboxylate (3.13 g, 14.48 mmol, Shanghai Bide) and N,N-diisopropylethylamine (3.74 g, 28.95 mmol) were added. The mixture was stirred at 80 °C for 17 hours. After cooling to room temperature, the reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system B to give the title compound 14d (3.68 g, 90.1% yield).

[0767] MS m / z(ESI):423.3[M+1].

[0768] Step 4

[0769] (S)-10-bromo-9-cyano-1,2,4a,5-tetrahydro-7H-pyrazino[2,1-c]pyridino[3,2-e][1,4]oxazopentane-3(4H)-carboxylic acid tert-butyl ester 14e

[0770] Compound 14d (3.8 g, 8.98 mmol) was dissolved in tetrahydrofuran (100 mL), and a 1 M diisobutylaluminum hydride solution in n-hexane (45 mL) was added dropwise at -78 °C. The mixture was allowed to return to room temperature naturally and stirred for 4 hours. A saturated potassium sodium tartrate solution (80 mL) was added to the reaction mixture, and the mixture was stirred for 30 minutes. The mixture was extracted with ethyl acetate (100 mL × 3), and the organic phases were combined and concentrated under reduced pressure. The residue was dissolved in dichloromethane (100 mL), and triethylsilane (3.13 g, 26.93 mmol) and trifluoroacetic acid (3.07 g, 26.93 mmol) were added. After stirring for 3 hours, the pH was adjusted to >7 with saturated sodium bicarbonate solution. The mixture was separated, and the aqueous phase was extracted with dichloromethane (50 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system B to give the title compound 14e (2.6 g, 70.7% yield).

[0771] MS m / z(ESI): 409.4 [M+1].

[0772] Step 5

[0773] (S)-10-bromo-3-(tert-butoxycarbonyl)-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyridino[3,2-e][1,4]oxazopentane-9-carboxylic acid 14f

[0774] Compound 14e (1.77 g, 4.32 mmol) was dissolved in ethanol (50 mL), and 5 M sodium hydroxide aqueous solution (2.6 mL) was added. The reaction mixture was reacted at 80 °C for 16 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure. Water (10 mL) was added to the residue, and the pH was adjusted to 6-7 with 1 N hydrochloric acid. The residue was extracted with ethyl acetate (50 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title compound 14f (1.62 g). The product was used directly in the next reaction without purification.

[0775] MS(ESI):428.3[M+H].

[0776] Step 6

[0777] (S)-10-bromo-9-(methoxy(methyl)aminocarbonyl)-1,2,4a,5-tetrahydro-7H-pyrazino[2,1-c]pyridino[3,2-e][1,4]oxazopentane-3(4H)-carboxylic acid tert-butyl ester 14g

[0778] Crude compound 14f (1.62 g, 3.78 mmol) and N,N-diethylethylamine (1.47 g, 11.35 mmol) were dissolved in N,N-dimethylformamide (15 mL). N-methoxymethylamine hydrochloride (554 mg, 5.68 mmol) and O-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (2.16 g, 5.67 mmol) were added at 0 °C, and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed successively with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system B to give the title compound 14f (1.4 g, 78.5% yield).

[0779] MS m / z(ESI):471.4[M+1].

[0780] Step 7

[0781] (S)-9-acetyl-10-bromo-1,2,4a,5-tetrahydro-7H-pyrazino[2,1-c]pyridino[3,2-e][1,4]oxazopentane-3(4H)-carboxylic acid tert-butyl ester 14h

[0782] 14 g (1.4 g, 2.97 mmol) of compound was dissolved in tetrahydrofuran (10 mL), and 2 mL of 3 M methyl magnesium bromide tetrahydrofuran solution was added at 0 °C. The mixture was allowed to return to room temperature and stirred for 2 hours. The reaction solution was quenched with saturated ammonium chloride solution, and extracted with ethyl acetate (20 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to give the title compound 14h (1 g, 79% yield).

[0783] MS m / z(ESI):426.3[M+1].

[0784] Step 8

[0785] (S)-10-bromo-9-((S)-1-hydroxyethyl)-1,2,4a,5-tetrahydro-7H-pyrazino[2,1-c]pyridino[3,2-e][1,4]oxazopentane-3(4H)-carboxylic acid tert-butyl ester 14i

[0786] Formic acid (265 mg, 5.64 mmol) was added to triethylamine (2.85 g, 28.15 mmol) at 0 °C. Under a nitrogen atmosphere, (S,S)-N-(p-toluenesulfonyl)-1,2-diphenylethanediamine (p-isopropylbenzene)ruthenium(II) chloride (15 mg, 23.6 μmol) was added, and the mixture was stirred at 40 °C for 15 min. After the reaction mixture cooled to room temperature, compound 14h (1 g, 2.35 mmol) was added, and the mixture was stirred at 40 °C for 2 h under a nitrogen atmosphere. After the reaction mixture cooled to room temperature, the mixture was concentrated under reduced pressure. The residue was extracted with saturated sodium chloride solution and ethyl acetate (30 mL × 3). The organic phases were combined and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to give the title compound 14i (992 mg, 98.7% yield).

[0787] MS m / z(ESI):428.4[M+1].

[0788] Step 9 (S)-10-bromo-9-((S)-1-methoxyethyl-1,2,4a,5-tetrahydro-7H-pyrazino[2,1-c]pyridino[3,2-e][1,4]oxazine-heptane-3(4H)-carboxylic acid tert-butyl ester 14j

[0789] Compound 14i (992 mg, 2.32 mmol) was dissolved in N,N-dimethylformamide (10 mL), sodium hydride (135 mg, 3.52 mmol, 60% purity) was added at 0 °C, and the mixture was stirred for 15 minutes while maintaining the temperature. Iodomethane (658 mg, 4.64 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with water and extracted with ethyl acetate (30 mL × 3). The organic phases were combined and washed successively with water and saturated sodium chloride solution. The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system B to give the title compound 14j (1 g, 97.6% yield).

[0790] MS m / z(ESI):442.4[M+1].

[0791] Step 10

[0792] (S)-10-bromo-9-((S)-1-methoxyethyl)-1,2,3,4,4a,5-tetrahydro-7H-pyrazino[2,1-c]pyridino[3,2-e][1,4]oxazetane 14k

[0793] Compound 14j (1 g, 2.26 mmol) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (2 mL) was added. The mixture was stirred for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was extracted with ethyl acetate (10 mL × 3) by adding saturated sodium bicarbonate solution. The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title compound 14k (775 mg). The product was used directly in the next reaction without purification.

[0794] MS m / z(ESI): 342.3 [M-1].

[0795] Step 11

[0796] (S)-10-bromo-9-((S)-1-methoxyethyl)-3-methyl-1,2,3,4,4a,5-tetrahydro-7H-pyrazino[2,1-c]pyridino[3,2-e][1,4]oxazetane 14l

[0797] The crude compound 14k (775 mg, 2.26 mmol) was dissolved in methanol (50 mL), and 37% formaldehyde aqueous solution (1.94 g, 22.61 mmol), sodium cyanoborohydride (406 mg, 6.79 mmol), and acetic acid (136 mg, 2.26 mmol) were added. The mixture was stirred for 17 hours. Saturated sodium bicarbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system B to give the title compound 14l (800 mg, 99.2% yield).

[0798] MS m / z(ESI): 356.3 [M-1].

[0799] Step Twelve

[0800] (S)-9-((S)-1-methoxyethyl)-3-methyl-10-(4,4,5,5-tetramethyl-1,3,2-dioxoborhexacyclopentan-2-yl)-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazetane 14m

[0801] Compound 14l (800 mg, 2.38 mmol) was dissolved in toluene (30 mL), and pinacol diboronate (1.82 g, 7.17 mmol), 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (175 mg, 0.24 mmol), and potassium acetate (1.17 g, 11.92 mmol) were added. The mixture was heated to 100 °C and stirred for 16 hours under a nitrogen atmosphere. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system B to give the title compound 14m (550 mg, 57.2% yield).

[0802] MS m / z(ESI): 404.4 [M+1].

[0803] Step Thirteen

[0804] (1r,2R,3S)-N-((6 3 S,4S,Z)-1 1 -Ethyl-1 2 -((S)-9-((S)-1-methoxyethyl)-3-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyridino[3,2-e][1,4]oxazopentane-10-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 64 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazo-1(5,3)-indolaz-6(1,3)-pyridazine-cycloundecaban-4-yl)-2,3-dimethylcyclopropane-1-carboxamide 14

[0805] M-(1r,2R,3S)-N-((6 3 S,4S,Z)-1 1 -Ethyl-1 2 -((S)-9-((S)-1-methoxyethyl)-3-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyridino[3,2-e][1,4]oxazopentane-10-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazo-1(5,3)-indolaz-6(1,3)-pyridazine-cycloundecaban-4-yl)-2,3-dimethylcyclopropane-1-carboxamide 14-p1

[0806] P-(1r,2R,3S)-N-((6 3 S,4S,Z)-1 1 -Ethyl-1 2 -((S)-9-((S)-1-methoxyethyl)-3-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyridino[3,2-e][1,4]oxazopentane-10-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazo-1(5,3)-indolaz-6(1,3)-pyridazine-cycloundecafen-4-yl)-2,3-dimethylcyclopropane-1-carboxamide 14-p2

[0807] Using steps fourteen to fifteen and eighteen to nineteen of the synthetic route in Example 1, the starting compound 1k in step fourteen was replaced with compound 14m, and the starting compound (1S,2S)-2-methylcyclopropane-1-carboxylic acid in step nineteen was replaced with compound (1r,2R,3S)-2,3-dimethylcyclopropane-1-carboxylic acid (Shanghai Bide) to obtain title compound 14 (148 mg). The title compound was purified by thin-layer silica gel chromatography with developing solvent system A to obtain title compound (21 mg, yield: 14.1%) and (35 mg, yield: 23.5%).

[0808] Single configuration compound (shorter retention time): (21 mg, yield: 14.1%).

[0809] MS m / z(ESI):868.0[M+1].

[0810] HPLC analysis: retention time 1.51 min, purity: 95% (column: Ultimate, C18, 1.8 μm, 2.1*50 mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%).

[0811] 1 H NMR (500MHz, CD3OD): δ8.58-8.57(m,1H),7.72-7.70(m,1H),7.56(s,1H),7.51-7.49(m,1H),7.36(s,1H),5.79-5.77(m,1H),5.06-5.05 (m,2H),4.48-4.45(m,1H),4.30-4.29(m,2H),4.24-4.21(m,2H),3.97-3.96(m,2H),3.74-3.71(m,2H),3.49-3.47(m,1H),3.08-3.07(m, 1H),2.91-2.87(m,1H),2.81-2.79(m,2H),2.60-2.57(m,3H),2.44(s,3H),2.19-2.17(m,2H),2.09-2.08(m,1H),1.98-1.97(m,1H),1.7 8-1.75(m,2H),1.62-1.60(m,2H),1.43-1.42(m,3H),1.39-1.31(m,6H),1.18-1.14(m,6H),1.02-1.01(m,3H),0.95(s,3H),0.47(s,3H).

[0812] Single-configuration compound (longer retention time): (35 mg, yield: 23.5%).

[0813] MS m / z(ESI):868.0[M+1].

[0814] HPLC analysis: retention time 1.52 min, purity: 95% (column: Ultimate, C18, 1.8 μm, 2.1*50 mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%).

[0815] 1 H NMR (500MHz, CD3OD): δ8.58-8.57(m,1H),7.72-7.70(m,1H),7.57(s,1H),7.48-7.46(m,2H),5.69-5.67(m,1H),5.06-5.05(m,2H),4 .48-4.45(m,1H),4.31-4.29(m,1H),4.11-4.06(m,2H),3.94-3.93(m,2H),3.81-3.71(m,3H),3.49-3.47(m,1H),3.27-3.21(m,4H),2 .83-2.82(m,1H),2.79-2.77(m,2H),2.58-2.55(m,3H),2.41(s,3H),2.27-2.25(m,1H),2.01-1.99(m,1H),1.79-1.77(m,1H),1.65-1 .63(m,1H),1.43-1.42(m,2H),1.38-1.36(m,2H),1.31-1.30(m,3H),1.27-1.24(m,6H),1.20-1.15(m,6H),1.02(s,3H),0.62(s,3H).

[0816] Example 15

[0817] (1r,2R,3S)-N-((6 4 S,4S,Z)-1 2 -((S)-9-((S)-1-methoxyethyl)-3-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyridino[3,2-e][1,4]oxazopentane-10-yl)-10,10-dimethyl-5,7-dioxo-1 1 -(2,2,2-trifluoroethyl)-1 1 H-8-Oza-6 2 6 3 -diaza-2(4,2)-thiazo-1(5,3)-indolaza-6(2,4)-bicyclo[3.1.1]heptaneheptan-1 / 2,3-dimethylcyclopropane-1-carboxamide 15

[0818] M-(1r,2R,3S)-N-((6 4 S,4S,Z)-1 2 -((S)-9-((S)-1-methoxyethyl)-3-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyridino[3,2-e][1,4]oxazopentane-10-yl)-10,10-dimethyl-5,7-dioxo-1 1 -(2,2,2-trifluoroethyl)-1 1 H-8-Oza-6 2 6 3 -diaza-2(4,2)-thiazo-1(5,3)-indolaza-6(2,4)-bicyclo[3.1.1]heptaneheptan-1 / 2,3-dimethylcyclopropane-1-carboxamide 15-p1

[0819] P-(1r,2R,3S)-N-((6 4 S,4S,Z)-1 2 -((S)-9-((S)-1-methoxyethyl)-3-methyl-1,2,3,4,4a,5-hexahydro

[0820] -7H-pyrazino[2,1-c]pyridino[3,2-e][1,4]oxazineheptane-10-yl)-10,10-dimethyl-5,7-dioxo-1 1 -(2,2,2-trifluoroethyl)-1 1 H-8-Oza-6 2 6 3 -diaza-2(4,2)-thiazo-1(5,3)-indolaza-6(2,4)-bicyclo[3.1.1]heptaneheptan-1 / 2,3-dimethylcyclopropane-1-carboxamide 15-p2

[0821] Using steps five through thirteen of the synthetic route in Example 16, the starting compound iodoethane in step five was replaced with 2,2,2-trifluoroethyltrifluoromethane sulfonate (Shanghai Bide) to obtain the title compound (25 mg, yield: 18.7%).

[0822] MS m / z(ESI): 933.0 [M+1].

[0823] 1H NMR (500MHz, CD3OD): δ8.48(s,1H),7.78-7.77(m,1H),7.63-7.61(m,2H),7.35(s,1H),5.59-5.58(m,1H),5.24-5.23(m,1H),5.03- 5.02(m,3H),4.87-4.84(m,2H),4.21-4.20(m,1H),3.95-3.93(m,2H),3.68-3.67(m,2H),3.43-3.42(m,1H),3.35-3.34(m,2H),3.32 -3.31(m,1H),3.23-3.21(m,1H),2.75-2.74(m,1H),2.72-2.71(m,2H),2.60-2.59(m,2H),2.49-2.47(m,3H),2.37(s,3H),2.21-2. 20(m,1H),1.62-1.61(m,1H),1.45-1.43(m,3H),1.42-1.30(m,6H),1.20-1.15(m,6H),0.96(s,3H),0.95-0.94(m,1H),0.42(s,3H).

[0824] Example 16

[0825] (1r,2R,3S)-N-((6 4 S,4S,Z)-1 1 -Ethyl-1 2 -((S)-9-((S)-1-methoxyethyl)-3-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyridino[3,2-e][1,4]oxazopentane-10-yl)-10,10-dimethyl-5,7-dioxo-1 1 H-8-Oza-6 2 6 3 -diaza-2(4,2)-thiazo-1(5,3)-indolaza-6(2,4)-bicyclo[3.1.1]heptaneheterocyclic undecaban-4-yl)-2,3-dimethylcyclopropane-1-carboxamide 16M-(1r,2R,3S)-N-((6 4 S,4S,Z)-1 1 -Ethyl-1 2 -((S)-9-((S)-1-methoxyethyl)-3-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyridino[3,2-e][1,4]oxazopentane-10-yl)-10,10-dimethyl-5,7-dioxo-1 1 H-8-Oza-6 26 3 -diaza-2(4,2)-thiazo-1(5,3)-indolaza-6(2,4)-bicyclo[3.1.1]heptaneheptan-16-pyrano-4-yl)-2,3-dimethylcyclopropane-1-carboxamide 16-p1

[0826] P-(1r,2R,3S)-N-((6 4 S,4S,Z)-1 1 -Ethyl-1 2 -((S)-9-((S)-1-methoxyethyl)-3-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyridino[3,2-e][1,4]oxazopentane-10-yl)-10,10-dimethyl-5,7-dioxo-1 1 H-8-Oza-6 2 6 3 -diaza-2(4,2)-thiazo-1(5,3)-indolaza-6(2,4)-bicyclo[3.1.1]heptaneheptan-16-p2

[0827] Step 1 (S)-2-((S)-3-(4-bromothiazol-2-yl)-2-((tert-butoxycarbonyl)amino)propionyl)-2,3-diazabicyclo[3.1.1]heptane-4-carboxylic acid methyl ester 16c

[0828] Methyl (S)-2,3-diazabicyclo[3.1.1]heptane-4-carboxylic acid ester di(2,2,2-trifluoroacetic acid) salt 16a (9.6 g, 24.99 mmol, prepared by the method disclosed in Reference Example 8 on page 64 of patent application "WO2024067857") was dissolved in dichloromethane (300 mL), and (S)-3-(4-bromothiazol-2-yl)-2-((tert-butoxycarbonyl)amino)propionic acid 16b (9.42 g) was added. 26.81 mmol (prepared using the method disclosed in Reference Example 1 on page 57 of patent application "WO2024067857") was added to N-methylmorpholine (25.27 g, 249.85 mmol) at 0 °C, followed by the addition of 1-hydroxybenzotriazole (761 mg, 5 mmol) and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (9.58 g, 49.97 mmol) in portions. The mixture was stirred at room temperature for 3 hours. Water was added to the reaction mixture, and the mixture was extracted with dichloromethane (100 mL × 3). The combined organic phases were concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system A to give the title compound 16c (7.4 g, yield: 61.1%).

[0829] MS m / z(ESI):489.2[M+1].

[0830] Step 2

[0831] (S)-10-bromo-9-((S)-1-methoxyethyl)-1,2,4a,5-tetrahydro-7H-pyrazino[2,1-c]pyridino[3,2-e][1,4]oxazopentane-3(4H)-carboxylic acid benzyl ester 16d

[0832] Compound 14k (1.5 g, 4.38 mmol) was dissolved in dichloromethane (40 mL), cooled to 0 °C, and triethylamine (1.33 g, 13.14 mmol) was added. Benzyl chloroformate (1.5 g, 8.76 mmol, Shanghai Titan) was added dropwise, and the mixture was allowed to return to room temperature with stirring for 17 hours. Saturated sodium bicarbonate solution (20 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (30 mL × 2). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system B to give the title compound 16d (2 g, 95.8% yield).

[0833] MS m / z(ESI):476.4[M+1].

[0834] Step 3

[0835] (S)-9-((S)-1-methoxyethyl)-10-(4,4,5,5-tetramethyl-1,3,2-dioxoborhexacyclopentan-2-yl)-1,2,4a,5-tetrahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazopentane-3(4H)-carboxylic acid benzyl ester 16e

[0836] Compound 16d (2.0 g, 4.2 mmol) was dissolved in toluene (60 mL), and pinacol diboronate (3.20 g, 12.60 mmol), 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (308 mg, 0.42 mmol), and potassium acetate (2.06 g, 20.99 mmol) were added. The mixture was heated to 100 °C and stirred for 16 hours under a nitrogen atmosphere. The reaction solution was cooled to room temperature, filtered, the filtrate was concentrated, and the residue was purified by silica gel column chromatography with eluent system B to give title compound 16e (2.2 g, 100% yield).

[0837] MS m / z(ESI): 524.5 [M+1].

[0838] Step 4

[0839] (S)-10-(5-bromo-3-(3-((tert-butyldiphenylsilyl)oxy)-2,2-dimethylpropyl)-1H-indol-2-yl)-9-((S)-1-methoxyethyl)-1,2,4a,5-tetrahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazopentane-3(4H)-carboxylic acid benzyl ester 16f

[0840] Compound 16e (2.2 g, 4.2 mmol) was dissolved in toluene (60 mL), and 5-bromo-3-(3-((tert-butyldiphenylsilyl)oxy)-2,2-dimethylpropyl)-2-iodo-1H-indole (2.72 g, 4.2 mmol, prepared by the method disclosed in Intermediate 1 on page 329 of patent application “US2021 / 130369”), 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (308 mg, 0.42 mmol) and potassium phosphate (2.23 g, 10.51 mmol) were added. The mixture was heated to 70 °C and stirred for 16 hours under a nitrogen atmosphere. The reaction solution was cooled to room temperature, filtered, the filtrate was concentrated, and the residue was purified by silica gel column chromatography with eluent system B to give title compound 16f (2.89 g, 75.1%).

[0841] MS m / z(ESI): 915.4 [M+1].

[0842] Step 5

[0843] (S)-10-(5-bromo-3-(3-((tert-butyldiphenylsilyl)oxy)-2,2-dimethylpropyl)-1-ethyl-1H-indol-2-yl)-9-((S)-1-methoxyethyl)-1,2,4a,5-tetrahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazopentane-3(4H)-carboxylic acid benzyl ester 16g

[0844] Compound 16f (1.3 g, 1.42 mmol) and cesium carbonate (1.39 g, 4.26 mmol) were dissolved in N,N-dimethylformamide (10 mL), and iodoethane (442 mg, 2.83 mmol) was added dropwise. The mixture was stirred for 5 hours. Saturated sodium bicarbonate solution (30 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (30 mL × 2). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography using eluent system B to give compound 16f (1.25 g, 76.5% yield).

[0845] MS m / z(ESI): 943.4 [M+1].

[0846] Step 6

[0847] M-(S)-10-(5-bromo-1-ethyl-3-(3-hydroxy-2,2-dimethylpropyl)-1H-indol-2-yl)-9-((S)-1-methoxyethyl)-1,2,4a,5-tetrahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazopentane-3(4H)-carboxylic acid benzyl ester 16i-1

[0848] P-(S)-10-(5-bromo-1-ethyl-3-(3-hydroxy-2,2-dimethylpropyl)-1H-indol-2-yl)-9-((S)-1-methoxyethyl)-1,2,4a,5-tetrahydro-7H-pyrazino[2,1-c]pyridino[3,2-e][1,4]oxazopentane-3(4H)-carboxylic acid benzyl ester 16i-2

[0849] 16 g (1.3 g, 1.37 mmol) of compound was dissolved in tetrahydrofuran (10 mL), and tetrabutylammonium fluoride (1.55 g, 6.88 mmol, Shanghai Titan) was added. The mixture was reacted at 50 °C for 16 hours. After the reaction solution was cooled to room temperature, it was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (50 mL), washed with water (50 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give crude compound 16 h (972 mg). The crude compound was purified by silica gel column chromatography with eluent system A to give the title compound (489 mg, yield: 50.3%, R). f ≈0.6), (317mg, yield: 32.6%, R f ≈0.3).

[0850] MS m / z(ESI): 705.4 [M+1].

[0851] Step 7

[0852] M-(S)-10-(1-ethyl-3-(3-hydroxy-2,2-dimethylpropyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxoborhexacyclopentan-2-yl)-1H-indol-2-yl)-9-((S)-1-methoxyethyl)-1,2,4a,5-tetrahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazopentane-3(4H)-carboxylic acid benzyl ester 16j-1 or

[0853] P-(S)-10-(1-ethyl-3-(3-hydroxy-2,2-dimethylpropyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxoborhexacyclopentan-2-yl)-1H-indol-2-yl)-9-((S)-1-methoxyethyl)-1,2,4a,5-tetrahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazopentane-3(4H)-carboxylic acid benzyl ester 16j-2

[0854] R in compounds 16i-1 and 16i-2 f The larger fraction (489 mg, 693 μmol) was dissolved in toluene (20 mL), and pinacol diboronate (530 mg, 2.09 mmol, Shaoyuan), 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (51 mg, 70 μmol), and potassium acetate (340 mg, 3.46 mmol) were added. The mixture was heated to 100 °C and stirred for 16 hours under a nitrogen atmosphere. The reaction solution was cooled to room temperature, filtered, the filtrate was concentrated, and the residue was purified by silica gel column chromatography using eluent system A to give the title compound (420 mg, yield: 80.5%).

[0855] MS m / z(ESI): 753.4 [M+1].

[0856] Step 8

[0857] M-(S)-10-(5-(2-((S)-2-((tert-butoxycarbonyl)amino)-3-((S)-4-(methoxycarbonyl)-2,3-diazabicyclo[3.1.1]hept-2-yl)-3-oxopropyl)thiazo-4-yl)-1-ethyl-3-(3-hydroxy-2,2-dimethylpropyl)-1H-indol-2-yl)-9-((S)-1-methoxyethyl)-1,2,4a,5-tetrahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazaheptan-3(4H)-carboxylic acid benzyl ester 16k-1 or

[0858] P-(S)-10-(5-(2-((S)-2-((tert-butoxycarbonyl)amino)-3-((S)-4-(methoxycarbonyl)-2,3-diazabicyclo[3.1.1]hept-2-yl)-3-oxopropyl)thiazo-4-yl)-1-ethyl-3-(3-hydroxy-2,2-dimethylpropyl)-1H-indol-2-yl)-9-((S)-1-methoxyethyl)-1,2,4a,5-tetrahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazaheptan-3(4H)-carboxylic acid benzyl ester 16k-2

[0859] Compounds 16j-1 or 16j-2 (420 mg, 558 μmol) were dissolved in a mixed solvent of toluene (5 mL), dioxane (15 mL), and water (5 mL). 16c (300 mg, 613 μmol), 1,1'-bis(diphenylphosphine)ferrocene palladium(II) dichloride (41 mg, 55 μmol), and potassium phosphate (296 mg, 1.39 mmol) were added. The mixture was heated to 70 °C and stirred for 16 hours under a nitrogen atmosphere. The reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate (20 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system A to give the title compound (380 mg, yield: 65.7%).

[0860] MS m / z(ESI):1035.6[M+1].

[0861] Step 9

[0862] M-(S)-2-((S)-3-(4-(2-((S)-3-((benzyloxy)carbonyl)-9-((S)-1-methoxyethyl)-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazaheptan-10-yl)-1-ethyl-3-(3-hydroxy-2,2-dimethylpropyl)-1H-indol-5-yl)thiazolyl)-2-((tert-butoxycarbonyl)amino)propionyl)-2,3-diazabicyclo[3.1.1]heptane-4-carboxylic acid 16l-1 or

[0863] P-(S)-2-((S)-3-(4-(2-((S)-3-((benzyloxy)carbonyl)-9-((S)-1-methoxyethyl)-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazaheptan-10-yl)-1-ethyl-3-(3-hydroxy-2,2-dimethylpropyl)-1H-indol-5-yl)thiazolyl)-2-((tert-butoxycarbonyl)amino)propionyl)-2,3-diazabicyclo[3.1.1]heptane-4-carboxylic acid 16l-2

[0864] Compound 16k⁻¹ or 16k⁻² (380 mg, 367 μmol) was dissolved in tetrahydrofuran (9 mL). A solution of lithium hydroxide monohydrate (78 mg, 1.86 mmol) in water (3 mL) was added at 0 °C, and the mixture was allowed to return to room temperature with stirring for 1 hour. The reaction solution was adjusted to pH < 7 with 1 M hydrochloric acid, extracted with ethyl acetate (15 mL × 3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title compound (350 mg). The product was used directly in the next reaction without purification.

[0865] MS m / z(ESI):1021.5[M+1].

[0866] Step 10

[0867] M-(4aS)-10-((6 4 S,4S,Z)-4-((tert-butoxycarbonyl)amino)-1 1 -Ethyl-10,10-dimethyl-5,7-dioxo-1 1 H-8-Oza-6 2 6 3 -diaza-2(4,2)-thiazo-1(5,3)-indolza-6(2,4)-bicyclo[3.1.1]heptaneheterocyclic undecaban-1 2 -yl)-9-((S)-1-methoxyethyl)-1,2,4a,5-tetrahydro-7H-pyrazino[2,1-c]pyridino[3,2-e][1,4]oxazopentane-3(4H)-carboxylic acid benzyl ester 16m-1 or

[0868] P-(4aS)-10-((6 4 S,4S,Z)-4-((tert-butoxycarbonyl)amino)-1 1 -Ethyl-10,10-dimethyl-5,7-dioxo-1 1 H-8-Oza-6 2 6 3 -diaza-2(4,2)-thiazo-1(5,3)-indolza-6(2,4)-bicyclo[3.1.1]heptaneheterocyclic undecaban-1 2 -9-((S)-1-methoxyethyl)-1,2,4a,5-tetrahydro-7H-pyrazino[2,1-c]pyridino[3,2-e][1,4]oxazopentane-3(4H)-carboxylic acid benzyl ester 16m-1

[0869] The crude compound 16l-1 or 16l-2 (350 mg, 343 μmol) was dissolved in acetonitrile (30 mL), and N-methylimidazole (281 mg, 3.42 mmol) and N,N,N',N'-tetramethylchloromethamphexane hexafluorophosphate (288 mg, 1.02 mmol) were added. The mixture was stirred for 1 hour. A saturated ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate (15 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The filtrate was then filtered again, concentrated, and the residue was purified by silica gel column chromatography with eluent system B to give the title compound (200 mg, yield: 58.1%). MS m / z (ESI): 1003.7 [M+1].

[0870] Step 11

[0871] M-((6 4 S,4S,Z)-1 1 -Ethyl-1 2 -((S)-9-((S)-1-methoxyethyl)-3-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyridino[3,2-e][1,4]oxazopentane-10-yl)-10,10-dimethyl-5,7-dioxo-1 1 H-8-Oza-6 2 6 3 -diaza-2(4,2)-thiazo-1(5,3)-indolaza-6(2,4)-bicyclo[3.1.1]heptaneheterocyclic undecaban-4-yl)tert-butyl carbamate 16n-1 or

[0872] P-((6 4 S,4S,Z)-1 1 -Ethyl-1 2 -((S)-9-((S)-1-methoxyethyl)-3-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyridino[3,2-e][1,4]oxazopentane-10-yl)-10,10-dimethyl-5,7-dioxo-1 1 H-8-Oza-6 2 6 3 -diaza-2(4,2)-thiazo-1(5,3)-indolaza-6(2,4)-bicyclo[3.1.1]heptaneheterocyclic undecaban-4-yl)tert-butyl carbamate 16n-2

[0873] Compound 16m-1 or 16m-2 (200 mg, 199 μmol) was dissolved in methanol (10 mL), paraformaldehyde (60 mg, 2.00 mmol, Sinopharm) and palladium hydroxide (196 mg) were added, the mixture was purged with hydrogen three times, stirred at room temperature for 17 hours, filtered, and the filtrate was concentrated under reduced pressure to obtain crude title compound (170 mg). The product was used directly in the next reaction without purification.

[0874] MS m / z(ESI): 883.5 [M+1].

[0875] Step Twelve

[0876] M-(6 4 (S,4S,Z)-4-amino-1 1 -Ethyl-1 2-((S)-9-((S)-1-methoxyethyl)-3-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyridino[3,2-e][1,4]oxazopentane-10-yl)-10,10-dimethyl-1 1 H-8-Oza-6 2 6 3 -diaza-2(4,2)-thiazo-1(5,3)-indolaza-6(2,4)-bicyclo[3.1.1]heptane heterocyclic undecaban-5,7-dione di(2,2,2-trifluoroacetic acid) salt 16o-1 or

[0877] P-(6 4 (S,4S,Z)-4-amino-1 1 -Ethyl-1 2 -((S)-9-((S)-1-methoxyethyl)-3-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyridino[3,2-e][1,4]oxazopentane-10-yl)-10,10-dimethyl-1 1 H-8-Oza-6 2 6 3 -diaza-2(4,2)-thiazo-1(5,3)-indolaza-6(2,4)-bicyclo[3.1.1]heptaneheterocyclic undecaban-5,7-dione di(2,2,2-trifluoroacetic acid) salt 16o-2

[0878] The crude compound 16n-1 or 16n-2 (170 mg, 192 μmol) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (5 mL) was added at 0 °C. The mixture was allowed to return to room temperature and stirred for 2 hours. The reaction solution was concentrated under reduced pressure to obtain the crude title compound (194 mg). The product was used directly in the next reaction without purification.

[0879] MS m / z(ESI): 783.5 [M+1].

[0880] Step Thirteen

[0881] M-(1r,2R,3S)-N-((6 4 S,4S,Z)-1 1 -Ethyl-1 2 -((S)-9-((S)-1-methoxyethyl)-3-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyridino[3,2-e][1,4]oxazopentane-10-yl)-10,10-dimethyl-5,7-dioxo-1 1 H-8-Oza-6 2 6 3-diaza-2(4,2)-thiazo-1(5,3)-indolaza-6(2,4)-bicyclo[3.1.1]heptaneheptan-1 / 2,3-dimethylcyclopropane-1-carboxamide 16-p1 or

[0882] P-(1r,2R,3S)-N-((6 4 S,4S,Z)-1 1 -Ethyl-1 2 -((S)-9-((S)-1-methoxyethyl)-3-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyridino[3,2-e][1,4]oxazopentane-10-yl)-10,10-dimethyl-5,7-dioxo-1 1 H-8-Oza-6 2 6 3 -diaza-2(4,2)-thiazo-1(5,3)-indolaza-6(2,4)-bicyclo[3.1.1]heptaneheptan-16-p2

[0883] The crude compound 16o-1 or 16o-2 (194 mg, 192 μmol) was dissolved in N,N-dimethylformamide (2 mL), and N,N-diisopropylethylamine (115 mg, 890 μmol) was added. (2R,3S)-2,3-dimethylcyclopropane-1-carboxylic acid (41 mg, 359 μmol) and 1-cyano-2-ethoxy-2-oxoethyleneaminooxy)dimethylamino-morpholino-carbomony hexafluorophosphate (114 mg, 266 μmol) were added at 0 °C, and the mixture was stirred for 2 hours. The reaction solution was purified by preparative high performance liquid chromatography (Waters-2545, column: Welch Xtimate C18, 30*250mm, 5μm; mobile phase: aqueous phase (10mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 40%-65%, flow rate: 30mL / min) to give the title compound (25mg, yield: 15.9%).

[0884] MS m / z(ESI): 879.9 [M+1].

[0885] 1H NMR (500MHz, CD3OD): δ8.46(s,1H),7.71(d,1H),7.58(s,1H),7.51(d,1H),7.37(s,1H),5.60(s,1H ),5.36(t,1H),4.67(q,1H),4.36-4.18(m,3H),4.03-3.92(m,1H),3.75-3.63(m,2H),3.08(d,1H),2 .81(d,2H),2.72(d,2H),2.67-2.56(m,2H),2.53-2.44(m,4H),2.37(s,3H),2.21(t,3H),2.05(d,2 H),1.67-1.54(m,3H),1.43(d,3H),1.24-1.12(m,9H),1.02(t,3H),0.96-0.87(m,6H),0.48(s,3H).

[0886] Example 17-1

[0887] M-(1r,2R,3S)-N-((3'S,4'S,Z)-1'-ethyl-2'-((S)-9-((S)-1-methoxyethyl)-3-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazopentane-10-yl)-10',10'-dimethyl-5',7'-dioxospiro[cyclopropane-1,3'-8-oxa-2(4,2)-thiazo-1(5,3-indolia-6(1,3-pyridazin-1,3-cyclohexane-1-undecano]-4'-yl)-2,3-dimethylcyclopropane-1-carboxamide 17-p1

[0888] P-(1r,2R,3S)-N-((3'S,4'S,Z)-1'-ethyl-2'-((S)-9-((S)-1-methoxyethyl)-3-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazopentane-10-yl)-10',10'-dimethyl-5',7'-dioxospiro[cyclopropane-1,3'-8-oxa-2(4,2)-thiazo-1(5,3-indolia-6(1,3-pyridazin-1,3-cyclohexane-1-undecano]-4'-yl)-2,3-dimethylcyclopropane-1-carboxamide 17-p2

[0889] first step

[0890] (S)-2-(1-(4-bromothiazo-2-yl)cyclopropyl)-2-((tert-butoxycarbonyl)amino)methyl acetate 13c-1

[0891] (R)-2-(1-(4-bromothiazo-2-yl)cyclopropyl)-2-((tert-butoxycarbonyl)amino)methyl acetate 13c-2

[0892] Compound 13c (30 g) was resolved by a chiral column (Shimadzu LC-20AP, column: ChiralPak IG, 10 μm, 50 mm * 300 mm; mobile phase A: n-hexane, mobile phase B: isopropanol, gradient ratio: A:B = 85:15, flow rate: 80 mL / min) to give title compounds 13c-2 (13.8 g, yield: 46%) and 13c-1 (13.5 g, yield: 45%).

[0893] Single configuration compound (shorter retention time): 13c-2 (13.8 g, yield: 46%).

[0894] Chiral HPLC analysis: retention time 4.046 min, purity: 99.9% (column: ChiralPak IG, 3*100mm, 3μm; mobile phase A: n-hexane, mobile phase B: isopropanol (0.1% diethylamine), gradient ratio: A:B = 85:15, flow rate: 1.5 mL / min).

[0895] Single configuration compound (longer retention time): 13c-1 (13.5 g, yield: 45%).

[0896] Chiral HPLC analysis: retention time 5.895 min, purity: 99.9% (column: ChiralPak IG, 3*100mm, 3μm; mobile phase A: n-hexane, mobile phase B: isopropanol (0.1% diethylamine), gradient ratio: A:B = 85:15, flow rate: 1.5 mL / min).

[0897] MS m / z(ESI):393.1[M+1].

[0898] Step 2

[0899] (S)-2-(1-(4-(3-(3-acetoxy-2,2-dimethylpropyl)-1H-indolyl-5-yl)thiazo-2-yl)cyclopropyl)-2-((tert-butoxycarbonyl)amino)methyl acetate 13e-1

[0900] Compound 13c-1 (2.06 g, 5.26 mmol) was dissolved in a mixed solvent of toluene (10 mL), 1,4-dioxane (40 mL), and water (10 mL). Then, 2,2-dimethyl-3-(5-(4,4,5,5-tetramethyl-1,3,2-dioxoborhexacyclopentan-2-yl)-1H-indol-3-yl)propyl acetate 13d (2.05 g, 5.52 mmol) was added, using the solution described on page 81 of patent application "WO2024067857". The reaction mixture was prepared by the method disclosed in Example 9, containing potassium phosphate (2.80 g, 13.19 mmol) and 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (385 mg, 5263 μmol). The mixture was stirred at 70 °C for 17 hours. The reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system E to give the title compound 13e-1 (2.30 g, 78.4% yield).

[0901] MS m / z(ESI): 556.7 [M+1].

[0902] Step 3

[0903] (S)-2-(1-(4-(3-(3-acetoxy-2,2-dimethylpropyl)-2-iodo-1H-indolyl-5-yl)thiazo-2-yl)cyclopropyl)-2-((tert-butoxycarbonyl)amino)methyl acetate 13f-1

[0904] Compound 13e-1 (1.98 g, 3.57 mmol) was dissolved in N,N-dimethylformamide (40 mL), and N-iodosuccinimide (763 mg, 3.39 mmol) was added. The mixture was stirred for 17 hours. The reaction solution was quenched with saturated sodium sulfite solution, extracted with ethyl acetate (30 mL × 3), and the organic phases were combined. The mixture was washed successively with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to give the title compound 13f-1 (1.69 g, 69.5% yield).

[0905] MS m / z(ESI): 682.1 [M+1].

[0906] Step 4

[0907] (S)-2-((tert-butoxycarbonyl)amino)-2-(1-(4-(3-(3-hydroxy-2,2-dimethylpropyl)-2-iodo-1H-indol-5-yl)thiazolyl)cyclopropyl)acetic acid 13g-1

[0908] Compound 13f-1 (1.69 g, 2.48 mmol) was dissolved in tetrahydrofuran (30 mL), and a solution of lithium hydroxide monohydrate (521 mg, 12.41 mmol) in water (9 mL) was added at 0 °C. The mixture was stirred at room temperature for 16 hours. The pH of the reaction solution was adjusted to approximately 6 with 1 M hydrochloric acid, and the mixture was extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude compound 13f-1 (1.69 g). The product was used directly in the next reaction without purification.

[0909] MS m / z(ESI): 626.1 [M+1].

[0910] Step 5

[0911] (S)-1-((S)-2-((tert-butoxycarbonyl)amino)-2-(1-(4-(3-(3-hydroxy-2,2-dimethylpropyl)-2-iodo-1H-indol-5-yl)thiazolyl)cyclopropyl)acetyl)hexahydropyridazine-3-carboxylic acid methyl ester 17a-1

[0912] (S)-hexahydropyridazine-3-carboxylic acid methyl ester hydrochloride (704 mg, 3.24 mmol, Shanghai Shaoyuan) was dissolved in dichloromethane (25 mL), and compound 13 g-1 (1.69 g, 2.70 mmol) was added. N,N-diisopropylethylamine (1.40 g, 10.83 mmol), n-butylphosphine anhydride (50% ethyl acetate solution) (3.89 g, 5.40 mmol), and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.41 g, 7.35 mmol) were added at 0 °C, and the reaction was stirred for 15 minutes while maintaining the temperature. The reaction mixture was quenched with water, extracted with dichloromethane (20 mL × 3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system A to give title compound 17a-1 (986 mg, yield: 48.5%).

[0913] MS m / z(ESI): 752.3 [M+1].

[0914] Step 6

[0915] (S)-1-((S)-2-((tert-butoxycarbonyl)amino)-2-(1-(4-(3-(3-hydroxy-2,2-dimethylpropyl)-2-iodo-1H-indol-5-yl)thiazolyl-2-yl)cyclopropyl)acetyl)hexahydropyridazine-3-carboxylic acid 17b-1

[0916] Compound 17a-1 (986 mg, 1.31 mmol) was dissolved in tetrahydrofuran (12 mL), and a solution of lithium hydroxide monohydrate (165 mg, 3.93 mmol) in water (3 mL) was added at 0 °C. The mixture was stirred and kept at the temperature for 2 hours. The pH of the reaction solution was adjusted to <7 with 1 M hydrochloric acid, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain crude title compound 17b-1 (1.1 g). The product was used directly in the next reaction without purification.

[0917] MS m / z(ESI):738.2[M+1].

[0918] Step 7

[0919] ((3'S,4'S,Z)-2'-iodo-10',10'-dimethyl-5',7'-dioxospiro[cyclopropane-1,3'-8-oxa-2(4,2)-thiazolidinium ...,4,2)-thiazolidinium-1,3'-8-oxa-2,4,2)-

[0920] -1(5,3)-Indolaz-6(1,3)-pyridazine-hexacyclic undecaphene]-4'-yl]tert-butyl carbamate 17c-1

[0921] The crude title compound 17b-1 (1.1 g, 1.49 mmol) was dissolved in dichloromethane (80 mL), and 1-hydroxybenzotriazole (1.13 g, 7.45 mmol) and N,N-diisopropylethylamine (3.64 g, 28.2 mmol) were added. The mixture was cooled to 0 °C, and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (4.29 g, 22.37 mmol) was added in portions. The mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched with saturated sodium bicarbonate solution, extracted with dichloromethane (15 mL × 3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to give title compound 17c-1 (450 mg, yield: 41.9%).

[0922] MS m / z(ESI):720.1[M+1].

[0923] Step 8

[0924] ((3'S,4'S,Z)-2'-((S)-9-((S)-1-methoxyethyl)-3-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazopentane-10-yl)-10',10'-dimethyl-5',7'-dioxospiro[cyclopropane-1,3'-8-oxa-2(4,2)-thiazo-1(5,3-indolia-6(1,3-pyridazinonecyclo[1,3]-4'-yl)tert-butyl carbamate 17d-1

[0925] Compound 14m (132 mg, 327 μmol), compound 17c-1 (236 mg, 328 μmol), 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (24 mg, 33 μmol), and potassium phosphate (174 mg, 820 μmol) were dissolved in toluene (5 mL), 1,4-dioxane (15 mL), and water (5 mL). The reaction was carried out at 70 °C for 16 hours under a nitrogen atmosphere. After the reaction solution was cooled to room temperature, it was diluted with ethyl acetate, and water was added. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate (10 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered to remove the desiccant, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system A to give the title compound 17d-1 (250 mg, yield: 87.7%).

[0926] MS m / z(ESI): 869.5 [M+1].

[0927] Step 9

[0928] ((3'S,4'S,Z)-1'-ethyl-2'-((S)-9-((S)-1-methoxyethyl)-3-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazopentane-10-yl)-10',10'-dimethyl-5',7'-dioxospiro[cyclopropane-1,3'-8-oxa-2(4,2)-thiazo-1(5,3-indolia-6(1,3-pyridazinonecyclo[1,3]-4'-yl)tert-butyl carbamate 17e-1

[0929] M-((3'S,4'S,Z)-1'-ethyl-2'-((S)-9-((S)-1-methoxyethyl)-3-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazopentane-10-yl)-10',10'-dimethyl-5',7'-dioxospiro[cyclopropane-1,3'-8-oxa-2(4,2)-thiazo-1(5,3)-indolia-6(1,3)-pyridazin-1-4'-yl)tert-butyl carbamate 17e-1-1

[0930] P-((3'S,4'S,Z)-1'-ethyl-2'-((S)-9-((S)-1-methoxyethyl)-3-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazopentane-10-yl)-10',10'-dimethyl-5',7'-dioxospiro[cyclopropane-1,3'-8-oxa-2(4,2)-thiazo-1(5,3)-indolia-6(1,3)-pyridazin-1-4'-yl)tert-butyl carbamate 17e-1-2

[0931] Compound 17d-1 (250 mg, 288 μmol) was dissolved in N,N-dimethylformamide (15 mL), and iodoethane (135 mg, 865 μmol) and cesium carbonate (421 mg, 1.29 mmol) were added. The mixture was stirred for 16 hours. The reaction solution was diluted with ethyl acetate and filtered. The filtrate was washed successively with water and saturated sodium chloride solution to separate the organic phase. The solution was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude title compound 17e-1 (258 mg). Purification was performed by preparative high-performance liquid chromatography (Waters-2545, column: Welch Xtimate C18, 30*150mm, 5μm; mobile phase: aqueous phase (10mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 40%-60%, flow rate: 30mL / min) to give the title compound (30mg, yield: 11.6%, denoted as compound A) and (88mg, yield: 34%, denoted as compound B).

[0932] Single-configuration compound (shorter retention time): (30 mg, yield: 11.6%, denoted as compound A).

[0933] MS m / z(ESI): 897.5 [M+1].

[0934] HPLC analysis: retention time 3.46 min, purity: 99% (column: Ultimate, C18, 1.8 μm, 2.1*50 mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%).

[0935] Single configuration compound (longer retention time): (88 mg, yield: 34%, denoted as compound B).

[0936] MS m / z(ESI): 897.5 [M+1].

[0937] HPLC analysis: Retention time 3.70 min, purity: 99% (Column: ACQUITY) C18, 1.7μm, 2.1*50mm; Mobile phase: water (10mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%).

[0938] Step 10

[0939] M-(3'S,4'S,Z)-4'-amino-1'-ethyl-2'-((S)-9-((S)-1-methoxyethyl)-3-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazopentane-10-yl)-10',10'-dimethylspiro[cyclopropane-1,3'-8-oxa-2(4,2)-thiazo-1(5,3)-indolia-6(1,3)-pyridazin-1,3'-dione hydrochloride

[0940] 17f-1-1

[0941] P-(3'S,4'S,Z)-4'-amino-1'-ethyl-2'-((S)-9-((S)-1-methoxyethyl)-3-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazopentane-10-yl)-10',10'-dimethylspiro[cyclopropane-1,3'-8-oxa-2(4,2)-thiazo-1(5,3)-indolia-6(1,3)-pyridazin-1,3'-dione hydrochloride

[0942] 17f-1-2

[0943] Compound A (30 mg, 33 μmol) was dissolved in dichloromethane (1 mL) and methanol (1 mL), and a 1,4-dioxane solution of 4M hydrogen chloride (5 mL) was added. The mixture was stirred for 2 hours, and the reaction solution was concentrated under reduced pressure to obtain the crude title compound (68 mg). The product was used directly in the next reaction without purification.

[0944] MS m / z(ESI): 797.5 [M+1].

[0945] Step 11

[0946] M-(1r,2R,3S)-N-((3'S,4'S,Z)-1'-ethyl-2'-((S)-9-((S)-1-methoxyethyl)-3-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazopentane-10-yl)-10',10'-dimethyl-5',7'-dioxospiro[cyclopropane-1,3'-8-oxa-2(4,2)-thiazo-1(5,3-indolia-6(1,3-pyridazin-1,3-cyclohexane-1-undecano]-4'-yl)-2,3-dimethylcyclopropane-1-carboxamide 17-p1

[0947] P-(1r,2R,3S)-N-((3'S,4'S,Z)-1'-ethyl-2'-((S)-9-((S)-1-methoxyethyl)-3-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazopentane-10-yl)-10',10'-dimethyl-5',7'-dioxospiro[cyclopropane-1,3'-8-oxa-2(4,2)-thiazo-1(5,3-indolia-6(1,3-pyridazin-1,3-cyclohexane-1-undecano]-4'-yl)-2,3-dimethylcyclopropane-1-carboxamide 17-p2

[0948] The crude compound 17f-1-1 or 17f-1-2 (68 mg, 85 μmol) obtained in the previous step was dissolved in N,N-dimethylformamide (4 mL), and N,N-diisopropylethylamine (55 mg, 425 μmol) was added. At 0 °C, (1r,2R,3S)-2,3-dimethylcyclopropane-1-carboxylic acid (10 mg, 88 μmol) and 1-cyano-2-ethoxy-2-oxoethyleneaminooxy)dimethylamino-morpholino-carbomony hexafluorophosphate (40 mg, 93 μmol) were added. The mixture was stirred at room temperature for 1 hour. The reaction solution was filtered, and the filtrate was purified by preparative high-performance liquid chromatography (Waters-2545, column: Welch Xtimate). C18, 30*150mm, 5μm; mobile phase: aqueous phase (10mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 40%-60%, flow rate: 30mL / min), to obtain the title compound (20mg, yield: 26.2%).

[0949] MS m / z(ESI): 893.5 [M+1].

[0950] 1 H NMR (500MHz, CD3OD): δ8.58(d,1H),7.69(dd,1H),7.48(s,1H),7.47(d,1H),7.40(s,1H),6.76(s,1H),5.09-4.99(m,2 H),4.92(d,1H),4.50-4.48(m,1H),4.25-4.20(m,2H),4.17-4.11(m,2H),4.03-3.93(m,2H),3.78(d,1H),3.61(d,1H) ,3.36-3.34(m,3H),3.22(s,2H),2.88-2.70(m,5H),2.53-2.46(m,2H),2.37(s,3H),2.20-2.18(m,1H),1.98-1.95(m, 1H),1.80(qt,1H),1.66(qd,1H),1.46-1.40(m,5H),1.38-1.26(m,4H),1.20-1.09(m,10H),0.85(s,3H),0.70(s,3H).

[0951] Example 17-2

[0952] M-(1r,2R,3S)-N-((3'S,4'S,Z)-1'-ethyl-2'-((S)-9-((S)-1-methoxyethyl)-3-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazopentane-10-yl)-10',10'-dimethyl-5',7'-dioxospiro[cyclopropane-1,3'-8-oxa-2(4,2)-thiazo-1(5,3-indolia-6(1,3-pyridazin-1,3-cyclohexane-1-undecano]-4'-yl)-2,3-dimethylcyclopropane-1-carboxamide 17-p1

[0953] P-(1r,2R,3S)-N-((3'S,4'S,Z)-1'-ethyl-2'-((S)-9-((S)-1-methoxyethyl)-3-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazopentane-10-yl)-10',10'-dimethyl-5',7'-dioxospiro[cyclopropane-1,3'-8-oxa-2(4,2)-thiazo-1(5,3-indolia-6(1,3-pyridazin-1,3-cyclohexane-1-undecano]-4'-yl)-2,3-dimethylcyclopropane-1-carboxamide 17-p2

[0954] Using steps 10 to 11 of the synthetic route in Example 17-1, the title compound (20 mg, yield: 15.5%) was obtained by replacing compound A in step 10 with compound B.

[0955] MS m / z(ESI): 893.5 [M+1].

[0956] 1 H NMR (500MHz, CD3OD): δ8.55(d,1H),7.69(dd,1H),7.53(s,1H),7.48(s,1H) ,7.45(d,1H),6.24(d,1H),5.10-5.00(m,2H),4.78(d,1H),4.51-4.45(m,1 H),4.42(dd,1H),4.12(q,1H),4.08-4.03(m,1H),3.96-3.93(m,2H),3.83- 3.76(m,1H),3.72(s,2H),3.28(s,3H),3.25-3.23(m,1H),3.20(d,1H),2.84 -2.81(m,1H),2.76(dt,2H),2.54-2.47(m,2H),2.45(d,1H),2.38(s,3H),2 .33-2.30(m,1H),2.05(s,2H),2.09-1.97(m,1H),1.86(qt,1H),1.80-1.73 (m,1H),1.64(qd,1H),1.45-1.39(m,1H),1.40-1.33(m,3H),1.30-1.23(m, 6H),1.20(d,3H),1.15(d,3H),1.04(s,3H),1.02-0.98(m,1H),0.62(s,3H).

[0957] Example 18

[0958] (1r,2R,3S)-N-((3'S,4'S,Z)-2'-((S)-9-((S)-1-methoxyethyl)-3-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazopentane-10-yl)-10',10'-dimethyl-5',7'-dioxo-1'-(2,2,2-trifluoroethyl)spiro[cyclopropane-1,3'-8-oxa-2(4,2)-thiazo-1(5,3)-indolaz-6(1,3)-pyridazin-1-cycloundecan]-4'-yl)-2,3-dimethylcyclopropane-1-carboxamide 18

[0959] M-(1r,2R,3S)-N-((3'S,4'S,Z)-2'-((S)-9-((S)-1-methoxyethyl)-3-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazopentane-10-yl)-10',10'-dimethyl-5',7'-dioxo-1'-(2,2,2-trifluoroethyl)spiro[cyclopropane-1,3'-8-oxa-2(4,2)-thiazo-1(5,3)-indolaz-6(1,3)-pyridazin-1-undecano]-4'-yl)-2,3-dimethylcyclopropane-1-carboxamide 18-p1

[0960] P-(1r,2R,3S)-N-((3'S,4'S,Z)-2'-((S)-9-((S)-1-methoxyethyl)-3-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazopentane-10-yl)-10',10'-dimethyl-5',7'-dioxo-1'-(2,2,2-trifluoroethyl)spiro[cyclopropane-1,3'-8-oxa-2(4,2)-thiazo-1(5,3)-indolaza-6(1,3-pyridazinane-1,3]-4'-yl)-2,3-dimethylcyclopropane-1-carboxamide 18-p2

[0961] Referring to the synthesis method in Example 17-1, the iodoethane in step nine was replaced with 2,2,2-trifluoroethyltrifluoromethane sulfonate (Shanghai Bide) to obtain the title compound.

[0962] MS m / z(ESI): 947.5 [M+1].

[0963] Example 19

[0964] M-(1r,2R,3S)-N-((6 4 S,4S,Z)-1 1 -Ethyl-1 2 -((R)-9-((S)-1-methoxyethyl)-3-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyridino[3,2-e][1,4]oxazopentane-10-yl)-10,10-dimethyl-5,7-dioxo-1 1 H-8-Oza-6 2 6 3 -diaza-2(4,2)-thiazoza-1(5,3)-indolza-6(2,4)-bicyclic

[0965] [3.1.1]Heptaneheterocyclic undecano-4-yl)-2,3-dimethylcyclopropane-1-carboxamide 19-p1

[0966] P-(1r,2R,3S)-N-((6 4 S,4S,Z)-1 1 -Ethyl-1 2 -((R)-9-((S)-1-methoxyethyl)-3-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyridino[3,2-e][1,4]oxazopentane-10-yl)-10,10-dimethyl-5,7-dioxo-1 1 H-8-Oza-6 2 6 3 -diaza-2(4,2)-thiazoza-1(5,3)-indolza-6(2,4)-bicyclic

[0967] [3.1.1]Heptaneheterocyclic undecano-4-yl)-2,3-dimethylcyclopropane-1-carboxamide 19-p2

[0968] first step

[0969] (R)-10-bromo-9-((S)-1-methoxyethyl)-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyridino[3,2-e][1,4]oxazineheptane 19a

[0970] Using steps three to ten of the synthetic route in Example 14, the starting compound (3S)-3-(hydroxymethyl)piperazine-1-carboxylic acid tert-butyl ester was replaced with compound (3R)-3-(hydroxymethyl)piperazine-1-carboxylic acid tert-butyl ester (Shanghai Titan) to obtain crude title compound 19a (2g).

[0971] MS m / z(ESI):342.1[M+1].

[0972] Step 2

[0973] (R)-9-((S)-1-methoxyethyl)-10-(4,4,5,5-tetramethyl-1,3,2-dioxoborhexacyclopentan-2-yl)-1,2,4a,5-tetrahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazopentane-3(4H)-carboxylic acid benzyl ester 19b

[0974] Using the synthetic route in Example 16, steps two and three were performed, replacing the starting material compound 14k in the second step with compound 19a to obtain crude title compound 19b (2.7 g, 98% yield).

[0975] MS m / z(ESI): 524.4 [M+1].

[0976] Step 3

[0977] M-(1r,2R,3S)-N-((6 4 S,4S,Z)-1 1 -Ethyl-1 2 -((R)-9-((S)-1-methoxyethyl)-3-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyridino[3,2-e][1,4]oxazopentane-10-yl)-10,10-dimethyl-5,7-dioxo-1 1 H-8-Oza-6 2 6 3 -diaza-2(4,2)-thiazo-1(5,3)-indolaza-6(2,4)-bicyclo[3.1.1]heptaneheptan-1 / 2,3-dimethylcyclopropane-1-carboxamide 19-p1

[0978] P-(1r,2R,3S)-N-((6 4 S,4S,Z)-1 1 -Ethyl-1 2 -((R)-9-((S)-1-methoxyethyl)-3-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyridino[3,2-e][1,4]oxazopentane-10-yl)-10,10-dimethyl-5,7-dioxo-1 1 H-8-Oza-6 2 6 3 -diaza-2(4,2)-thiazo-1(5,3)-indolaza-6(2,4)-bicyclo[3.1.1]heptaneheptan-1 / 2,3-dimethylcyclopropane-1-carboxamide 19-p2

[0979] Following steps 11 to 19 of the synthetic route in Example 1, the starting compound 1m in step 11 was replaced with compound 16a, the starting compound 1k in step 14 was replaced with compound 19b, and the starting compound (1S,2S)-2-methylcyclopropane-1-carboxylic acid in step 19 was replaced with (1r,2R,3S)-2,3-dimethylcyclopropane-1-carboxylic acid to obtain crude title compound 19 (48 mg). Purification was performed by preparative high-performance liquid chromatography (Waters-2545, column: Welch Xtimate C18, 30*150 mm, 5 μm; mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 40%-60%, flow rate: 30 mL / min) to obtain the title compound (15 mg, yield: 30.9%) and (5 mg, yield: 10.3%).

[0980] Single configuration compound (shorter retention time): (15 mg, yield: 30.9%).

[0981] MS m / z(ESI): 879.4 [M+1].

[0982] HPLC analysis: retention time 1.68 min, purity: 99% (column: Ultimate, C18, 1.8 μm, 2.1*50 mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%).

[0983] 1H NMR (500MHz, CD3OD): δ8.46-8.45(m,1H),7.72-7.70(m,1H),7.58(s,1H),7 .50-7.48(m,2H),5.92-5.90(m,1H),5.46-5.44(m,1H),5.09-5.00(m,2H), 4.79-4.76(m,1H),4.69-4.67(m,1H),4.12-4.04(m,2H),3.98-3.97(m,2H) ,3.89-3.82(m,1H),3.72-3.65(m,2H),3.43-3.39(m,1H),3.30-3.29(m,2H) ,3.25(s,3H),3.21-3.18(m,1H),2.80-2.76(m,2H),2.73-2.70(m,1H),2.6 6-2.63(m,1H),2.50-2.46(m,3H),2.44-2.41(m,1H),2.37(s,3H),2.23-2. 19(m,1H),1.72-1.68(m,1H),1.48-1.45(m,1H),1.42-1.38(m,1H),1.34-1 .26(m,8H),1.21-1.19(m,3H),1.17-1.17(m,3H),1.00(s,3H),0.59(s,3H).

[0984] Single-configuration compound (longer retention time): (5 mg, yield: 10.3%).

[0985] MS m / z(ESI): 879.4 [M+1].

[0986] HPLC analysis: Retention time 1.73 min, purity: 99% (Column: ACQUITY) C18, 1.7μm, 2.1*50mm; Mobile phase: water (10mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%).

[0987] 1H NMR(500MHz,CD3OD):8.47-8.46(m,1H),7.71-7.69(m,1H),7.57(s,1H), 7.51-7.49(m,1H),7.38(s,1H),5.62-5.60(m,1H),5.04-5.02(m,2H),4. 69-4.67(m,1H),4.63-4.61(m,1H),4.32-4.25(m,2H),4.19-4.14(m,1H) ,3.96-3.95(m,2H),3.75-3.73(m,1H),3.67-3.65(m,1H),3.46-3.42(m, 1H),3.09-3.06(m,1H),2.81-2.79(m,1H),2.77-2.67(m,3H),2.61-2.57 (m,1H),2.49-2.45(m,3H),2.37(s,3H),2.24-2.20(m,2H),2.06-2.05(m ,1H),1.62-1.56(m,2H),1.47-1.45(m,3H),1.42-1.31(m,8H),1.19-1.1 8(m,3H),1.16-1.15(m,3H),1.01-0.99(m,2H),0.93(s,3H),0.53(s,3H).

[0988] Example 20

[0989] M-(2S)-2-cyclopentyl-2-((S)-7-((2R,3R)-3-cyclopropyl-1-methylazacyclopropane-2-carbonyl)-2,7-diazaspiro[4.4]non-2-yl)-N-((6 4 S,4S,Z)-1 2 -((S)-9-((S)-1-methoxyethyl)-3-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyridino[3,2-e][1,4]oxazopentane-10-yl)-10,10-dimethyl-5,7-dioxo-1 1 -(2,2,2-trifluoroethyl)-1 1 H-8-Oza-6 2 6 3 -diaza-2(4,2)-thiazo-1(5,3)-indolza-6(2,4)-

[0990] Bicyclic [3.1.1]heptanylheterocyclic undecano-4-yl)acetamide 20-p1

[0991] P-(2S)-2-cyclopentyl-2-((S)-7-((2R,3R)-3-cyclopropyl-1-methylazacyclopropane-2-carbonyl)-2,7-diazaspiro[4.4]non-2-yl)-N-((6 4 S,4S,Z)-1 2 -((S)-9-((S)-1-methoxyethyl)-3-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyridino[3,2-e][1,4]oxazopentane-10-yl)-10,10-dimethyl-5,7-dioxo-1 1 -(2,2,2-trifluoroethyl)-1 1 H-8-Oza-6 2 6 3 -diaza-2(4,2)-thiazo-1(5,3)-indolza-6(2,4)-

[0992] Bicyclic [3.1.1]heptanylheterocyclic undecano-4-yl)acetamide 20-p2

[0993] Referring to Example 22, iodoethane was replaced with 2,2,2-trifluoroethyltrifluoromethane sulfonate (Shanghai Bide) to obtain the title compound.

[0994] MS m / z(ESI): 1194.2 [M+1].

[0995] Example 21

[0996] M-(2S)-2-cyclopentyl-2-((S)-7-((2R,3R)-3-cyclopropyl-1-methylazacyclopropane-2-carbonyl)-2,7-diazaspiro[4.4]non-2-yl)-N-((2 2 S,6 4 S,4S)-1 2 -((S)-9-((S)-1-methoxyethyl)-3-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyridino[3,2-e][1,4]oxazopentane-10-yl)-10,10-dimethyl-5,7-dioxo-1 1 -(2,2,2-trifluoroethyl)-1 1 H-8-Oza-6 2 6 3 -diaza-2(4,2)-morpholina-1(5,3)-indola-6(2,4)-bicyclo[3.1.1]heptaneheterocyclic undecaban-4-yl)acetamide 21-p1

[0997] P-(2S)-2-cyclopentyl-2-((S)-7-((2R,3R)-3-cyclopropyl-1-methylazacyclopropane-2-carbonyl)-2,7-diazaspiro[4.4]non-2-yl)-N-((2 2 S,6 4 S,4S)-1 2 -((S)-9-((S)-1-methoxyethyl)-3-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyridino[3,2-e][1,4]oxazopentane-10-yl)-10,10-dimethyl-5,7-dioxo-1 1 -(2,2,2-trifluoroethyl)-1 1 H-8-Oza-6 2 6 3 -diaza-2(4,2)-morpholina-1(5,3)-indola-6(2,4)-bicyclo[3.1.1]heptaneheterocyclic undecaban-4-yl)acetamide 21-p2

[0998] MS m / z(ESI):1196.2[M+1].

[0999] Example 22

[1000] M-(2S)-2-cyclopentyl-2-((S)-7-((2R,3R)-3-cyclopropyl-1-methylazacyclopropane-2-carbonyl)-2,7-diazaspiro[4.4]non-2-yl)-N-((6 4 S,4S,Z)-1 1 -Ethyl-1 2 -((S)-9-((S)-1-methoxyethyl)-3-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyridino[3,2-e][1,4]oxazopentane-10-yl)-10,10-dimethyl-5,7-dioxo-1 1 H-8-Oza-6 2 6 3 -diaza-2(4,2)-thiazo-1(5,3)-indolaza-6(2,4)-bicyclo[3.1.1]heptaneheterocyclic undecaban-4-yl)acetamide 22-p1

[1001] P-(2S)-2-cyclopentyl-2-((S)-7-((2R,3R)-3-cyclopropyl-1-methylazacyclopropane-2-carbonyl)-2,7-diazaspiro[4.4]non-2-yl)-N-((6 4 S,4S,Z)-1 1 -Ethyl-1 2-((S)-9-((S)-1-methoxyethyl)-3-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyridino[3,2-e][1,4]oxazopentane-10-yl)-10,10-dimethyl-5,7-dioxo-1 1 H-8-Oza-6 2 6 3 -diaza-2(4,2)-thiazo-1(5,3)-indolaza-6(2,4)-bicyclo[3.1.1]heptaneheterocyclic undecaban-4-yl)acetamide 22-p2

[1002] first step

[1003] M-(5S)-7-((1S)-1-cyclopentyl-2-(((6) 4 S,4S,Z)-1 1 -Ethyl-1 2 -((S)-9-((S)-1-methoxyethyl)-3-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyridino[3,2-e][1,4]oxazopentane-10-yl)-10,10-dimethyl-5,7-dioxo-1 1 H-8-Oza-6 2 6 3 -diaza-2(4,2)-thiazoza-1(5,3)-indolza-6(2,4)-bicyclo[3.1.1]heptaneheterocyclic undecaban-4-yl)amino)-2-oxoethyl)-2,7-diazaspiro[4.4]nonane-2-carboxylic acid tert-butyl ester 22a-1

[1004] P-(5S)-7-((1S)-1-cyclopentyl-2-(((6) 4 S,4S,Z)-1 1 -Ethyl-1 2 -((S)-9-((S)-1-methoxyethyl)-3-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyridino[3,2-e][1,4]oxazopentane-10-yl)-10,10-dimethyl-5,7-dioxo-1 1 H-8-Oza-6 2 6 3 -diaza-2(4,2)-thiazoza-1(5,3)-indolza-6(2,4)-bicyclo[3.1.1]heptaneheterocyclic undecaban-4-yl)amino)-2-oxoethyl)-2,7-diazaspiro[4.4]nonane-2-carboxylic acid tert-butyl ester 22a-2

[1005] The crude compound 16o-1 or 16o-2 (40 mg, 51 μmol) was obtained from R in compounds 16i-1 and 16i-2. f The larger component was dissolved in N,N-dimethylformamide (1 mL), and N,N-diisopropylethylamine (33 mg, 255 μmol) was added. At 0 °C, (S)-2-((S)-7-(tert-butoxycarbonyl)-2,7-diazaspiro[4.4]non-2-yl)-2-cyclopentylacetic acid (18 mg, 51 μmol, prepared by the method disclosed in Intermediate A-3 and A-4 on page 166 of the specification in patent application "WO2023060253") and 1-cyano-2-ethoxy-2-oxoethyleneaminooxy)dimethylamino-morpholino-carbomony hexafluorophosphate (28 mg, 66 μmol) were added. The mixture was stirred at room temperature for 2 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate (5 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system E to give the title compound (7 mg, yield: 12.2%).

[1006] MS m / z(ESI):1117.7[M+1].

[1007] Step 2

[1008] M-(2S)-2-cyclopentyl-N-((6 4 S,4S,Z)-1 1 -Ethyl-1 2 -((S)-9-((S)-1-methoxyethyl)-3-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyridino[3,2-e][1,4]oxazopentane-10-yl)-10,10-dimethyl-5,7-dioxo-1 1 H-8-Oza-6 2 6 3 -diaza-2(4,2)-thiazo-1(5,3)-indolaza-6(2,4)-bicyclo[3.1.1]heptaneheterocyclic undecapan-4-yl)-2-((S)-2,7-diazaspiro[4.4]non-2-yl)acetamide dihydrochloride 22b-1

[1009] P-(2S)-2-cyclopentyl-N-((6 4 S,4S,Z)-1 1 -Ethyl-1 2-((S)-9-((S)-1-methoxyethyl)-3-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyridino[3,2-e][1,4]oxazopentane-10-yl)-10,10-dimethyl-5,7-dioxo-1 1 H-8-Oza-6 2 6 3 -diaza-2(4,2)-thiazo-1(5,3)-indolza-6(2,4)-bicyclo[3.1.1]heptaneheterocyclic undecapon-4-yl)-2-((S)-2,7-diazaspiro[4.4]non-2-yl)acetamide dihydrochloride 22b-2

[1010] Compound 22a-1 or 22a-2 (7 mg, 6 μmol) was dissolved in dichloromethane (0.5 mL), and a 1,4-dioxane solution of 4 M hydrogen chloride (0.5 mL) was added. The mixture was stirred for 1 hour, and the reaction solution was concentrated under reduced pressure to obtain the crude title compound (7 mg). The product was used directly in the next reaction without purification.

[1011] MS m / z(ESI):1017.7[M+1].

[1012] Step 3

[1013] M-(2S)-2-cyclopentyl-2-((S)-7-((2R,3R)-3-cyclopropyl-1-methylazacyclopropane-2-carbonyl)-2,7-diazaspiro[4.4]non-2-yl)-N-((6 4 S,4S,Z)-1 1 -Ethyl-1 2 -((S)-9-((S)-1-methoxyethyl)-3-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyridino[3,2-e][1,4]oxazopentane-10-yl)-10,10-dimethyl-5,7-dioxo-1 1 H-8-Oza-6 2 6 3 -diaza-2(4,2)-thiazo-1(5,3)-indolaza-6(2,4)-bicyclo[3.1.1]heptaneheterocyclic undecaban-4-yl)acetamide 22-p1

[1014] P-(2S)-2-cyclopentyl-2-((S)-7-((2R,3R)-3-cyclopropyl-1-methylazacyclopropane-2-carbonyl)-2,7-diazaspiro[4.4]non-2-yl)-N-((6 4 S,4S,Z)-1 1 -Ethyl-1 2-((S)-9-((S)-1-methoxyethyl)-3-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyridino[3,2-e][1,4]oxazopentane-10-yl)-10,10-dimethyl-5,7-dioxo-1 1 H-8-Oza-6 2 6 3 -diaza-2(4,2)-thiazo-1(5,3)-indolaza-6(2,4)-bicyclo[3.1.1]heptaneheterocyclic undecaban-4-yl)acetamide 22-p2

[1015] The crude compound 22b-1 or 22b-2 (7 mg, 6 μmol) was dissolved in N,N-dimethylformamide (0.5 mL), and N,N-diisopropylethylamine (7 mg, 55 μmol) was added. At 0 °C, (2R,3R)-3-cyclopropyl-1-methylazacyclopropane-2-carboxylic acid (2.4 mg, 17 μmol, prepared using the method disclosed in Intermediate A-5 on page 53 of patent application "WO2022235866") and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (4 mg, 10.3 μmol) were added. The reaction mixture was stirred for 2 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography (Waters-2545, column: Welch Xtimate). C18, 30×150mm, 5μm; mobile phase: aqueous phase (10mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 40%-60%, flow rate: 30mL / min) to give the title compound (3mg, yield: 38.4%).

[1016] MS m / z(ESI): 1140.7 [M+1].

[1017] 1H NMR (500MHz, CD3OD): δ8.49(d,1H),7.73(ddd,1H),7.62(s,1H),7.52(dd,1H),7. 37(s,1H),5.98(t,1H),5.61(s,1H),5.36(dd,1H),5.09–4.99(m,2H),4.74(s,2H ),4.71–4.65(m,1H),4.36–4.21(m,4H),3.97(t,2H),3.70–3.64(m,4H),3.61–3. 47(m,3H),3.44(d,3H),3.12(d,1H),3.04(t,1H),3.02–2.92(m,2H),2.86–2.69(m ,5H),2.67–2.57(m,2H),2.50(q,3H),2.40(s,1H),2.37(s,2H),2.34(d,2H),2.3 1(s,1H),2.31–2.18(m,3H),2.05(d,1H),1.99(d,1H),1.94–1.90(m,1H),1.90–1 .80(m,3H),1.67–1.58(m,4H),1.52–1.39(m,5H),1.35(s,3H),1.01(t,2H),0.94 (d,2H),0.91(d,2H),0.67(qd,2H),0.58–0.48(m,2H),0.46(s,2H),0.28(dd,1H).

[1018] Example 23

[1019] M-(2S)-2-cyclopentyl-2-((S)-7-((2R,3R)-3-cyclopropyl-1-methylazacyclopropane-2-carbonyl)-2,7-diazaspiro[4.4]non-2-yl)-N-((3'S,4'S,Z)-1'-ethyl-2'-((S)-9-((S)-1-methoxyethyl)-3-methyl-1,2,3,4,4a ,5-Hexahydro-7H-pyrazino[2,1-c]pyridino[3,2-e][1,4]oxazheptan-10-yl)-10',10'-dimethyl-5',7'-dioxospiro[cyclopropane-1,3'-8-oxa-2(4,2)-thiazo-1(5,3)-indolia-6(1,3)-pyridazine-hexacycloundecan]-4'-yl)acetamide 23-p1

[1020] P-(2S)-2-cyclopentyl-2-((S)-7-((2R,3R)-3-cyclopropyl-1-methylazacyclopropane-2-carbonyl)-2,7-diazaspiro[4.4]non-2-yl)-N-((3'S,4'S,Z)-1'-ethyl-2'-((S)-9-((S)-1-methoxyethyl)-3-methyl-1,2,3,4,4a ,5-Hexahydro-7H-pyrazino[2,1-c]pyridino[3,2-e][1,4]oxazheptan-10-yl)-10',10'-dimethyl-5',7'-dioxospiro[cyclopropane-1,3'-8-oxa-2(4,2)-thiazo-1(5,3)-indolia-6(1,3)-pyridazine-hexacycloundecan]-4'-yl)acetamide 23-p2

[1021] first step

[1022] M-(5S)-7-((1S)-1-cyclopentyl-2-(((3'S,4'S,Z)-1'-ethyl-2'-((S)-9-((S)-1-methoxyethyl)-3-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazheptan-10-yl)-10',10'-dimethyl-5',7'-dioxaspiro[cyclopropane-1,3'-8-oxa-2(4,2)-thiazo-1(5,3)-indolia-6(1,3)-pyrazinocycloundecan]-4'-yl)amino)-2-oxoethyl)-2,7-diazaspiro[4,4]nonane-2-carboxylic acid tert-butyl ester 23a-1 P-(5S)-7-((1S)-1-cyclopentyl-2-(((3'S,4'S,Z)-1'-ethyl-2'-((S)-9-((S)-1-methoxyethyl)-3-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazheptan-10-yl)-10',10'-dimethyl-5',7'-dioxaspiro[cyclopropane-1,3'-8-oxa-2(4,2)-thiazo-1(5,3)-indolia-6(1,3)-pyrazinocycloundecan]-4'-yl)amino)-2-oxoethyl)-2,7-diazaspiro[4,4]nonane-2-carboxylic acid tert-butyl ester 23a-2

[1023] The crude compound 17f-1-1 or 17f-1-2 (26 mg, 32 μmol, prepared from the components with shorter retention times of compounds 17e-1-1 and 17e-1-2 in step nine of Example 17-1) was dissolved in N,N-dimethylformamide (1 mL), and N,N-diisopropylethylamine (63 mg, 487 μmol) was added. At 0 °C, (S)-2-((S)-7-(tert-butoxycarbonyl)-2,7-diazaspiro[4.4]non-2-yl)-2-cyclopentylacetic acid (14 mg, 40 μmol, prepared using Intermediate A-3 and...) was added on page 166 of the specification in patent application "WO2023060253". The compound was prepared by the method disclosed in A-4 and reacted with O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (19 mg, 50 μmol) at room temperature with stirring for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (5 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system E to give the title compound (36 mg, yield: 97.5%).

[1024] MS m / z(ESI):1131.6[M+1].

[1025] Step 2

[1026] M-(2S)-2-cyclopentyl-N-((3'S,4'S,Z)-1'-ethyl-2'-((S)-9-((S)-1-methoxyethyl)-3-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazheptan-10-yl)-10',10'-dimethyl-5',7'-dioxospiro[cyclopropane-1,3'-8-oxa-2(4,2)-thiazo-1(5,3)-indolia-6(1,3)-pyridazin-4'-yl)-2-((S)-2,7-diazaspiro[4,4]non-2-yl)acetamide 23b-1

[1027] P-(2S)-2-cyclopentyl-N-((3'S,4'S,Z)-1'-ethyl-2'-((S)-9-((S)-1-methoxyethyl)-3-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazheptan-10-yl)-10',10'-dimethyl-5',7'-dioxospiro[cyclopropane-1,3'-8-oxaz-2(4,2)-thiazo-1(5,3)-indolaz-6(1,3-pyridazin-1,3]-4'-yl)-2-((S)-2,7-diazaspiro[4,4]non-2-yl)acetamide 23b-2

[1028] Compound 23a-1 or 23a-2 (36 mg, 31.8 μmol) was dissolved in dichloromethane (0.5 mL), and a 4M solution of 1,4-dioxane (0.5 mL) containing hydrogen chloride was added. The mixture was stirred for 1 hour. The reaction solution was concentrated under reduced pressure to obtain the crude title compound (32 mg). The product was used directly in the next reaction without purification.

[1029] MS m / z(ESI): 1031.7 [M+1].

[1030] Step 3

[1031] M-(2S)-2-cyclopentyl-2-((S)-7-((2R,3R)-3-cyclopropyl-1-methylazacyclopropane-2-carbonyl)-2,7-diazaspiro[4.4]non-2-yl)-N-((3'S,4'S,Z)-1'-ethyl-2'-((S)-9-((S)-1-methoxyethyl)-3-methyl-1,2,3,4,4a ,5-Hexahydro-7H-pyrazino[2,1-c]pyridino[3,2-e][1,4]oxazheptan-10-yl)-10',10'-dimethyl-5',7'-dioxospiro[cyclopropane-1,3'-8-oxa-2(4,2)-thiazo-1(5,3)-indolia-6(1,3)-pyridazine-hexacycloundecan]-4'-yl)acetamide 23-p1

[1032] P-(2S)-2-cyclopentyl-2-((S)-7-((2R,3R)-3-cyclopropyl-1-methylazacyclopropane-2-carbonyl)-2,7-diazaspiro[4.4]non-2-yl)-N-((3'S,4'S,Z)-1'-ethyl-2'-((S)-9-((S)-1-methoxyethyl)-3-methyl-1,2,3,4,4a ,5-Hexahydro-7H-pyrazino[2,1-c]pyridino[3,2-e][1,4]oxazheptan-10-yl)-10',10'-dimethyl-5',7'-dioxospiro[cyclopropane-1,3'-8-oxa-2(4,2)-thiazo-1(5,3)-indolia-6(1,3)-pyridazine-hexacycloundecan]-4'-yl)acetamide 23-p2

[1033] The crude compound 23b-1 or 23b-2 (33 mg, 31 μmol) was dissolved in N,N-dimethylformamide (1.5 mL), and N,N-diisopropylethylamine (83 mg, 129 μmol) was added. At 0 °C, lithium (2R,3R)-3-cyclopropyl-1-methylazacyclopropane-2-carboxylate (19 mg, 17 μmol, prepared by the method disclosed in Intermediate A-5 on page 53 of patent application "WO2022235866") and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (18 mg, 47 μmol) were added, and the reaction was stirred for 2 hours. The reaction solution was filtered and purified by high performance liquid chromatography (Waters-2545, column: Welch Xtimate C18, 30×150mm, 5μm; mobile phase: aqueous phase (10mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 40%-60%, flow rate: 30mL / min) to give the title compound (9mg, yield: 24.3%).

[1034] MS m / z(ESI):1154.7[M+1].

[1035] 1H NMR (500MHz, CD3OD): δ8.64(s,1H),7.70(ddd,1H),7.60–7.45(m,2H),7.40(d,1H),5.31–4.97(m,3H),4.48(d,2H),4. 36–4.10(m,5H),4.07–3.91(m,2H),3.80(d,2H),3.68–3.58(m,2H),3.48–3.28(m,5H),3.27–3.15(m,4H),3.05(dd,1H ),2.92–2.46(m,11H),2.39(d,4H),2.32(s,2H),2.24(dd,2H),2.10–1.90(m,1H),1.88–1.71(m,6H),1.69–1.58(m,3H ),1.44(d,3H),1.40–1.28(m,4H),1.20–1.09(m,6H),0.85(s,3H),0.74–0.57(m,6H),0.53–0.37(m,3H),0.25(dt,1H).

[1036] Example 24

[1037] MN-((1S)-1-cyclopentyl-2-(((3'S,4'S,Z)-1'-ethyl-2'-((S)-9-((S)-1-methoxyethyl)-3-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyridino[3,2-e][1,4]oxazopentane-10-yl)-10',10'- Dimethyl-5',7'-dioxospiro[cyclopropane-1,3'-8-oxa-2(4,2)-thiazo-1(5,3-indolia-6(1,3-pyridazin-cycloundecan]-4'-yl)amino)-2-oxoethyl)-1-(4-(dimethylamino)-4-methylpentan-2-ynyl)-4-fluoro-N-methylpiperidine-4-carboxamide 24-p1

[1038] PN-((1S)-1-cyclopentyl-2-(((3'S,4'S,Z)-1'-ethyl-2'-((S)-9-((S)-1-methoxyethyl)-3-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyridino[3,2-e][1,4]oxazopentane-10-yl)-10',10'- Dimethyl-5',7'-dioxospiro[cyclopropane-1,3'-8-oxa-2(4,2)-thiazo-1(5,3-indolia-6(1,3-pyridazin-cycloundecan]-4'-yl)amino)-2-oxoethyl)-1-(4-(dimethylamino)-4-methylpentan-2-ynyl)-4-fluoro-N-methylpiperidine-4-carboxamide 24-p2

[1039] first step

[1040] (S)-2-((tert-butoxycarbonyl)(methyl)amino)-2-cyclopentylacetate methyl ester 24b

[1041] (S)-2-((tert-butoxycarbonyl)(methyl)amino)-2-cyclopentylacetic acid (900 mg, 3.50 mmol, prepared by the method disclosed in "Organic Letters, 2023, vol. 25, #43, p. 7822-7826") was dissolved in tetrahydrofuran (10 mL) and methanol (10 mL), and a 2M solution of (trimethylsilyl)diazomethane in n-hexane (3.5 mL) was added. The mixture was stirred for 2 hours, and the reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system A to give the title compound 24b (680 mg, yield: 71.6%).

[1042] MS m / z(ESI):172.3[M-99].

[1043] Step 2

[1044] (S)-2-Cyclopentyl-2-(methylamino)acetic acid methyl ester hydrochloride 24c

[1045] Compound 24b (680 mg, 2.51 mmol) was dissolved in dichloromethane (5 mL), and a 1,4-dioxane solution of 4M hydrogen chloride (2 mL) was added. The mixture was stirred for 1 hour, and the reaction solution was concentrated under reduced pressure to obtain crude title compound 24c (400 mg). The product was used directly in the next reaction without purification.

[1046] MS m / z(ESI): 172.3 [M+1].

[1047] Step 3

[1048] (S)-4-((1-cyclopentyl-2-methoxy-2-oxoethyl)(methyl)aminocarbonyl)-4-fluoropiperidine-1-carboxylic acid tert-butyl ester 24d

[1049] N-(tert-butoxycarbonyl)-4-fluoropiperidine-4-carboxylic acid (500 mg, 2.02 mmol, Shanghai Titan) was dissolved in dichloromethane (7 mL), and oxalyl chloride (307 mg, 2.42 mmol) and 2 drops of N,N-dimethylformamide were added. After stirring for 1 hour, triethylamine (818 mg, 8.08 mmol) and crude compound 51c (400 mg, 1.92 mmol) were added and stirred for 1 hour. Water was added to the reaction solution, and the mixture was extracted with dichloromethane (10 mL × 3). The organic phases were combined, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to give the title compound 24d (500 mg, yield: 61.7%).

[1050] MS m / z(ESI): 345.4 [M-55].

[1051] Step 4

[1052] (S)-2-cyclopentyl-2-(4-fluoro-N-methylpiperidin-4-carboxamido)methyl acetate 2,2,2-trifluoroacetate 24e

[1053] Compound 24d (500 mg, 1.25 mmol) was dissolved in dichloromethane (8 mL), and trifluoroacetic acid (4 mL) was added. The mixture was stirred for 1 hour, and the reaction solution was concentrated under reduced pressure to obtain crude title compound 24e (520 mg). The product was used directly in the next reaction without purification.

[1054] MS m / z(ESI): 301.4 [M+1].

[1055] Step 5: (S)-2-cyclopentyl-2-(1-(4-(dimethylamino)-4-methylpentan-2-ynyl)-4-fluoro-N-methylpiperidin-4-carboxamido)methyl acetate 24f

[1056] The crude compound 24e (250 mg, 603 μmol), sodium 4-(dimethylamino)-4-methyl-2-pentyneate (246 mg, 1.38 mmol, Shanghai Bide), and triethylamine (402 mg, 3.97 mmol) were dissolved in N,N-dimethylformamide (4 mL). Butylphosphine anhydride (50% ethyl acetate solution) (600 mg, 833 μmol) was added under ice bath conditions, and the mixture was stirred for 1 hour. Water was added to the reaction mixture, and the solution was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system A to give the title compound 24f (150 mg, yield: 41.2%).

[1057] MS m / z(ESI): 438.5 [M+1].

[1058] Step 6: (S)-2-cyclopentyl-2-(1-(4-(dimethylamino)-4-methylpentan-2-ynyl)-4-fluoro-N-methylpiperidin-4-carboxamido)acetic acid 24g

[1059] Compound 24f (150 mg, 343 μmol) was dissolved in tetrahydrofuran (4 mL) and water (4 mL). Sodium hydroxide (30 mg, 715 μmol) was added at 0 °C. The mixture was allowed to return to room temperature and stirred for 3 hours. The reaction solution was concentrated under reduced pressure to remove the organic solvent. The residual liquid was adjusted to pH < 7 with 0.5 M hydrochloric acid, extracted with dichloromethane (10 mL × 2), and concentrated under reduced pressure in aqueous phase to obtain crude title compound 24 g (120 mg). The product was used directly in the next reaction without purification.

[1060] MS m / z(ESI): 424.5 [M+1].

[1061] Step 7

[1062] MN-((1S)-1-cyclopentyl-2-(((3'S,4'S,Z)-1'-ethyl-2'-((S)-9-((S)-1-methoxyethyl)-3-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyridino[3,2-e][1,4]oxazopentane-10-yl)-10',10'- Dimethyl-5',7'-dioxospiro[cyclopropane-1,3'-8-oxa-2(4,2)-thiazo-1(5,3-indolia-6(1,3-pyridazin-cycloundecan]-4'-yl)amino)-2-oxoethyl)-1-(4-(dimethylamino)-4-methylpentan-2-ynyl)-4-fluoro-N-methylpiperidine-4-carboxamide 24-p1

[1063] PN-((1S)-1-cyclopentyl-2-(((3'S,4'S,Z)-1'-ethyl-2'-((S)-9-((S)-1-methoxyethyl)-3-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyridino[3,2-e][1,4]oxazopentane-10-yl)-10',10'- Dimethyl-5',7'-dioxospiro[cyclopropane-1,3'-8-oxa-2(4,2)-thiazo-1(5,3-indolia-6(1,3-pyridazin-cycloundecan]-4'-yl)amino)-2-oxoethyl)-1-(4-(dimethylamino)-4-methylpentan-2-ynyl)-4-fluoro-N-methylpiperidine-4-carboxamide 24-p2

[1064] Using the synthetic route in Example 17-1, the starting compound (1r,2R,3S)-2,3-dimethylcyclopropane-1-carboxylic acid in step eleven was replaced with compound 24g to obtain the title compound (26mg, yield: 25.7%).

[1065] 1 H NMR(500MHz,CD3OD)δ8.58-8.57(m,1H),7.72-7.67(m,1H),7.50-7.48(m,2H),7.41-7.40(m,1H),6 .80-6.67(m,2H),5.06(s,2H),4.79-4.73(m,1H),4.62-4.58(m,1H),4.49-4.47(m,1H),4.37-4.31 (m,2H),4.25-4.14(m,4H),3.98-3.97(m,2H),3.80-3.74(m,1H),3.64-3.62(m,1H),3.37-3.35(m, 2H),3.27-3.26(m,1H),3.22-3.19(m,3H),3.14-3.13(m,2H),2.92-2.85(m,4H),2.77-2.74(m,1H) ,2.67-2.65(m,2H),2.61-2.55(m,1H),2.48(s,3H),2.43(s,3H),2.38(s,3H),2.30-2.28(m,1H),2 .23-2.2(m,2H),2.12-2.06(m,2H),2.00-1.97(m,1H),1.84-1.82(m,2H),1.74-1.73(m,1H),1.67- 1.60(m,5H),1.52(s,3H),1.48(s,3H),1.45-1.44(m,3H),1.35-1.31(m,5H),1.29-1.24(m,2H),1. 20-1.19(m,1H),1.14-1.09(m,5H),0.93-0.89(m,2H),0.85-0.83(m,1H),0.71(m,1H),0.63(m,1H).

[1066] MS m / z(ESI): 1202.7 [M+1].

[1067] Example 25

[1068] M-(2S)-2-cyclopentyl-2-((S)-7-((2R,3R)-3-cyclopropyl-1-methylazacyclopropane-2-carbonyl)-2,7-diazaspiro[4.4]non-2-yl)-N-((3'S,4'S,Z)-2'-((S)-9-((S)-1-methoxyethyl)-3-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazine) [2,1-c]pyrido[3,2-e][1,4]oxazheptan-10-yl)-10',10'-dimethyl-5',7'-dioxo-1'-(2,2,2-trifluoroethyl)spiro[cyclopropane-1,3'-8-oxa-2(4,2)-thiazo-1(5,3)-indolaz-6(1,3)-pyridazine-hexacycloundecan]-4'-yl)acetamide 25-p1

[1069] P-(2S)-2-cyclopentyl-2-((S)-7-((2R,3R)-3-cyclopropyl-1-methylazacyclopropane-2-carbonyl)-2,7-diazaspiro[4.4]non-2-yl)-N-((3'S,4'S,Z)-2'-((S)-9-((S)-1-methoxyethyl)-3-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazine) [2,1-c]pyrido[3,2-e][1,4]oxazheptan-10-yl)-10',10'-dimethyl-5',7'-dioxo-1'-(2,2,2-trifluoroethyl)spiro[cyclopropane-1,3'-8-oxa-2(4,2)-thiazo-1(5,3)-indolaz-6(1,3)-pyridazine-hexacycloundecan]-4'-yl)acetamide 25-p2

[1070] first step

[1071] M-(S)-10-(3-(3-hydroxy-2,2-dimethylpropyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxoborhexacyclopentan-2-yl)-1-(2,2,2-trifluoroethyl)-1H-indol-2-yl)-9-((S)-1-methoxyethyl)-1,2,4a,5-tetrahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazopentane-3(4H)-carboxylic acid benzyl ester 25a-1

[1072] P-(S)-10-(3-(3-hydroxy-2,2-dimethylpropyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxoborhexacyclopentan-2-yl)-1-(2,2,2-trifluoroethyl)-1H-indol-2-yl)-9-((S)-1-methoxyethyl)-1,2,4a,5-tetrahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazopentane-3(4H)-carboxylic acid benzyl ester 25a-2

[1073] Using steps five through seven of the synthetic route in Example 16, the starting compound iodoethane in step five was replaced with 2,2,2-trifluoroethyltrifluoromethanesulfonate (Shanghai Bide) to obtain the title compound 25a-1 or 25a-2 (690 mg, yield: 86%).

[1074] MS m / z(ESI): 807.6 [M+1].

[1075] Step 2

[1076] M-(4aS)-10-((3'S,4'S,Z)-4'-((tert-butoxycarbonyl)amino)-10',10'-dimethyl-5',7'-dioxo-1'-(2,2,2-trifluoroethyl)spiro[cyclopropane-1,3'-8-oxa-2(4,2)-thiazo-1(5,3-indolazo-6(1,3-pyridazin-hexacycloundecanedan]-2'-yl)-9-((S)-1-methoxyethyl)-1,2,4a,5-tetrahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazopentane-3(4H)-carboxylic acid benzyl ester 25b-1

[1077] P-(4aS)-10-((3'S,4'S,Z)-4'-((tert-butoxycarbonyl)amino)-10',10'-dimethyl-5',7'-dioxo-1'-(2,2,2-trifluoroethyl)spiro[cyclopropane-1,3'-8-oxa-2(4,2)-thiazo-1(5,3-indolazo-6(1,3-pyridazin-hexacycloundecan]-2'-yl)-9-((S)-1-methoxyethyl)-1,2,4a,5-tetrahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazopentane-3(4H)-carboxylic acid benzyl ester 25b-2

[1078] Using the synthetic route in Example 17-1, steps 2, 4 to 7, the starting compound 13d in step 2 was replaced with 25a-1 or 25a-2 to obtain the title compound 25b-1 or 25b-2 (230 mg, yield: 45.8%).

[1079] MS m / z(ESI): 1071.6 [M+1].

[1080] Step 3

[1081] M-(3'S,4'S,Z)-4'-amino-2'-((S)-9-((S)-1-methoxyethyl)-3-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazopentane-10-yl)-10',10'-dimethyl-1'-(2,2,2-trifluoroethyl)spiro[cyclopropane-1,3'-8-oxa-2(4,2)-thiazo-1(5,3)-indolia-6(1,3)-pyridazin-1,3'-hexacycloundecanedan]-5',7'-dionebis(2,2,2-trifluoroacetate)25c-1

[1082] P-(3'S,4'S,Z)-4'-amino-2'-((S)-9-((S)-1-methoxyethyl)-3-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazopentane-10-yl)-10',10'-dimethyl-1'-(2,2,2-trifluoroethyl)spiro[cyclopropane-1,3'-8-oxa-2(4,2)-thiazo-1(5,3)-indolia-6(1,3)-pyridazin-1,3'-hexacycloundecanedan]-5',7'-dionebis(2,2,2-trifluoroacetate)25c-2

[1083] Using steps 11 and 12 of the synthetic route in Example 16, the starting compound 16m-1 or 16m-2 in step 11 was replaced with 25b-1 or 25b-2 to obtain the title compound 25c-1 or 25c-2 (57 mg, yield: 37.4%). The product was used directly in the next reaction without purification.

[1084] MS m / z(ESI): 851.7 [M+1].

[1085] Step 4

[1086] M-(2S)-2-cyclopentyl-2-((S)-7-((2R,3R)-3-cyclopropyl-1-methylazacyclopropane-2-carbonyl)-2,7-diazaspiro[4.4]non-2-yl)-N-((3'S,4'S,Z)-2'-((S)-9-((S)-1-methoxyethyl)-3-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazine) [2,1-c]pyrido[3,2-e][1,4]oxazheptan-10-yl)-10',10'-dimethyl-5',7'-dioxo-1'-(2,2,2-trifluoroethyl)spiro[cyclopropane-1,3'-8-oxa-2(4,2)-thiazo-1(5,3)-indolaz-6(1,3)-pyridazine-hexacycloundecan]-4'-yl)acetamide 25-p1

[1087] P-(2S)-2-cyclopentyl-2-((S)-7-((2R,3R)-3-cyclopropyl-1-methylazacyclopropane-2-carbonyl)-2,7-diazaspiro[4.4]non-2-yl)-N-((3'S,4'S,Z)-2'-((S)-9-((S)-1-methoxyethyl)-3-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazine) [2,1-c]pyrido[3,2-e][1,4]oxazheptan-10-yl)-10',10'-dimethyl-5',7'-dioxo-1'-(2,2,2-trifluoroethyl)spiro[cyclopropane-1,3'-8-oxa-2(4,2)-thiazo-1(5,3)-indolaz-6(1,3)-pyridazine-hexacycloundecan]-4'-yl)acetamide 25-p2

[1088] Using the synthetic route in Example 22, the first-step starting compound 16o-1 or 16o-1 was replaced with 25c-1 or 25c-2 to obtain the title compound (57 mg, yield: 37.4%).

[1089] MS m / z(ESI):1208.7[M+1].

[1090] 1H NMR (500MHz, CD3OD): δ8.62(s,1H),7.77(ddd,1H),7.67–7.50(m,2H),7.38(s,1H),5.22–4.89(m,5H),4.46(d ,1H),4.29(s,1H),4.15(d,1H),4.08–3.90(m,2H),3.87–3.61(m,3H),3.56–3.34(m,6H),3.29–3.15(m,3H),3. 08(dd,1H),2.99–2.61(m,11H),2.50(dt,2H),2.39(d,5H),2.30(d,3H),2.00(d,2H),1.90–1.73(m,6H),1.74– 1.48(m,6H),1.44(d,4H),1.37–1.26(m,1H),1.21–1.08(m,2H),0.96(s,3H),0.79–0.38(m,9H),0.27(dt,1H).

[1091] Example 26

[1092] M-(2S)-2-cyclopentyl-2-((S)-7-((2R,3R)-3-cyclopropyl-1-methylazacyclopropane-2-carbonyl)-2,7-diazaspiro[4.4]non-2-yl)-N-((6 3 S,4S,Z)-1 1 -Ethyl-1 2 -((S)-9-((S)-1-methoxyethyl)-3-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyridino[3,2-e][1,4]oxazopentane-10-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazo-1(5,3)-indolaz-6(1,3)-pyridazine-hexacycloundecaban-4-yl)acetamide 26-p1

[1093] P-(2S)-2-cyclopentyl-2-((S)-7-((2R,3R)-3-cyclopropyl-1-methylazacyclopropane-2-carbonyl)-2,7-diazaspiro[4.4]non-2-yl)-N-((6 3 S,4S,Z)-1 1 -Ethyl-1 2-((S)-9-((S)-1-methoxyethyl)-3-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyridino[3,2-e][1,4]oxazopentane-10-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazo-1(5,3)-indolaz-6(1,3)-pyridazine-cycloundecaban-4-yl)acetamide 26-p2

[1094] first step

[1095] M-(6 3 (S,4S,Z)-4-amino-1 1 -Ethyl-1 2 -((S)-9-((S)-1-methoxyethyl)-3-methyl-1,2,3,4,4a,...

Claims

A compound of general formula (I) or a pharmaceutically acceptable salt thereof. in: X and Y may be the same or different, and each is independently selected from (CR). 4a R 4b ) m NR 5 (CR 4c R 4d ) r’ C(O)NR 5 NR 5 C(O), C(O) and O(CR) 4e R 4f ) n’ ; m can be 0, 1, 2, 3, or 4; n' can be 0, 1, 2, 3 or 4; r' can be 0, 1, 2, 3 or 4; R 4a R 4b R 4c R 4d R 4e and R 4f They may be the same or different, and each is independently selected from hydrogen atoms or R. 4aa ; Each R 4aa The same or different, and each independently selected from halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, cyano, amino, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are optionally substituted by one or more R*; or two R* groups. 4aa Together with the attached atoms, it forms cycloalkyl, heterocyclic, aryl, or heteroaryl groups, or R 4aa R D Together with the attached atom, it forms a cycloalkyl or heterocyclic group, wherein the cycloalkyl, heterocyclic, aryl or heteroaryl group is optionally substituted by one or more R*; R 5 R d and R R The same or different, and each independently selected from hydrogen atom, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkylalkyl, heterocyclic alkyl, arylalkyl, heteroarylalkyl, cycloalkylenyl, heterocyclic alkenyl, aryl alkenyl, heteroaryl alkenyl, cycloalkylynyl, heterocyclic ynylynyl, arylynylynyl, and heteroarylynyl, wherein the alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkylalkyl, heterocyclic alkyl, arylalkyl, heteroarylalkyl, cycloalkylenyl, heterocyclic alkenyl, aryl alkenyl, heteroaryl alkenyl, cycloalkylynyl, heterocyclic ynylynyl, arylynylynyl, and heteroarylynyl are each independently optionally selected from halogen, oxo, =S, =NR. 64 Alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, -NR 9a R 9b The alkyl group is substituted with one or more of the following: hydroxyl, hydroxyalkyl, cycloalkyl optionally substituted with one or more R*, heterocyclic group optionally substituted with one or more R*, aryl group optionally substituted with one or more R*, heteroaryl group optionally substituted with one or more R*, cycloalkylalkyl optionally substituted with one or more R*, heterocyclic alkyl optionally substituted with one or more R*, arylalkyl optionally substituted with one or more R*, and heteroarylalkyl optionally substituted with one or more R*; or R 4a R 4b R 4c R 4d R 4e R 4f and R 5 The two atoms in the group together with the attached atoms form a cycloalkyl, heterocyclic, aryl, or heteroaryl group, wherein the cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally substituted by one or more R*. G 1 G 2 G 3 and G 4 One of them is a carbon atom attached to ring B, and the other three are the same or different, and each is independently CH, CR 6 Or N; Ring A is a heterocyclic group; Ring B and ring C may be the same or different, and each is independently selected from cycloalkyl, heterocyclic, aryl or heteroaryl groups; R A R B R C R D and R 6 They may be the same or different, and each is independently selected from halogen, alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, -NR 7a R 7b -NR 7a OR 7b -ONR 7a R 7b -NR 7c NR 7a R 7b hydroxyl group, -C(O)R 8 -C(O)OR 8 -C(O)NR 7a R 7b -S(O) w R 8 , Oxide group, =S, =NOR 61 =CR 62 R 63 =NR 64 Cycloalkyl, heterocyclic, aryl, and heteroaryl, wherein the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each independently and optionally selected from halogen, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, -NR 9a R 9b The substance is substituted by one or more substituents selected from hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl; or Two Rs A Together with the attached atoms, it forms a cycloalkyl, heterocyclic, aryl, or heteroaryl group, wherein the cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally surrounded by one or more R groups. AA Replace; or Two Rs D Together with the attached atoms, it forms cycloalkyl, heterocyclic, aryl, or heteroaryl groups, or R D R d The atoms bonded together form a heterocyclic group, wherein the cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally bonded by one or more R groups. DD replace; R 2 Selected from O, NH and N-alkyl; L 2 The alkylene group is optionally alkylene oxide (R0) or alkylene oxide (R0) by one or more R0. L2 replace; R L2 Same or different, and each independently selected from halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, cyano, amino, hydroxy, hydroxyalkyl, oxo, =S, =NOR 61 =CR 62 R 63 =NR 64 Cycloalkyl, heterocyclic, aryl, and heteroaryl groups, wherein the alkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are optionally substituted with one or more R* groups; or Two Rs L2 Together with the attached atoms, it forms a cycloalkyl, heterocyclic, aryl, or heteroaryl group, wherein the cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally surrounded by one or more R groups. LL2 replace; L 1 It is an alkylene or cycloalkyl group, wherein the alkylene or cycloalkyl group is optionally surrounded by one or more R groups. L1 replace; L is R 10 or R 11 and R 12 The same or different, and each independently selected from hydrogen atoms, halogens, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, cyano, amino, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are optionally separated by one or more R E replace; L 3 For key or -N(R) L3 )C(O)-; L 4 For bonds or -(alkylene) y -N(R L4 )C(=O)-; R 10 Selected from alkyl, cycloalkyl, heterocyclic and NR 101 R 102 The alkyl, cycloalkyl, and heterocyclic groups are each independently and optionally influenced by one or more R groups. F replace; Each R F They may be the same or different, and each is independently selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, -NR 7a R 7b hydroxyl group, oxo group, =S, =NOR 61 =CR 62 R 63 =NR 64 cycloalkyl, heterocyclic, aryl, heteroaryl, -C(O)R F1 -C(O)OR F1 -C(O)NR F2 R F3 -S(O) w R F1 and -S(O) w OR F1 The alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each independently and optionally converted by one or more R groups. FF replace; R 61 R 62 R 63 and R 64 The same or different, and each independently selected from hydrogen atoms, halogens, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, hydroxyl, hydroxyalkyl, and cycloalkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, and heterocyclic groups are each independently optionally selected by one or more R # Replace; or R 63 R 62 Together with the attached atoms, they form cycloalkyl or heterocyclic groups, each of which is optionally independently bound by one or more R groups. FF replace; R 7a R 7b R 7c R 9a R 9b R L3 R L4 R 101 R 102 R F2 and R F3 They may be the same or different, and each is independently selected from hydrogen atoms, alkyl, heteroalkyl, hydroxyalkyl, aminoalkyl, cycloalkyl and heterocyclic groups, wherein each of the alkyl, cycloalkyl and heterocyclic groups is independently optionally substituted by one or more substituents selected from halogen, alkyl, alkoxy, haloalkyl and haloalkoxy; Or R 7a and R 7b It forms a heterocyclic group together with the attached nitrogen atom, or R 9a and R 9b It forms a heterocyclic group together with the attached nitrogen atom, or R 101 and R 102 It forms a heterocyclic group together with the attached nitrogen atom, or R F2 and R F3 Together with the attached nitrogen atom, a heterocyclic group is formed, wherein the heterocyclic group is optionally substituted by one or more substituents selected from halogen, oxo, =S, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl. R 8 and R F1 The same or different, and each independently selected from hydrogen atoms, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, cycloalkyl, and heterocyclic groups, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, and heterocyclic groups are each independently optionally selected by one or more R atoms. # replace; Each R*, R AA R DD R LL2 R L1 R E R FF and R # The same or different, and each independently selected from oxo, =S, =N-alkyl, =NH, halogen, alkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, cyano, alkylthio, amino, -NHalkyl, -N(alkyl)2, -alkylene-amino, -alkylene-NHalkyl, -alkylene-N(alkyl)2, amide, nitro, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkylalkyl, heterocyclic alkyl, arylalkyl, heteroarylalkyl, cycloalkyloxy, heterocyclic oxy, aryloxy, and heteroaryloxy, wherein the =N-alkyl, alkyl, alkenyl, alkoxy, alkoxyalkyl, alkoxyalkyl, alkylthio, -NHalkyl, -N(alkyl)2, -alkylene-amino, -alkylene-NHalkyl, -alkylene The alkyl-N(alkyl)2, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkylalkyl, heterocyclicalkyl, arylalkyl, heteroarylalkyl, cycloalkyloxy, heterocyclicoxy, aryloxy and heteroaryloxy are each independently and optionally substituted by one or more substituents selected from oxo, =S, halogen, alkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, cyano, alkylthio, amino, -NHalkyl, -N(alkyl)2, -alkylene-amino, -alkylene-NHalkyl, -alkylene-N(alkyl)2, amide, nitro, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkylalkyl, heterocyclicalkyl, arylalkyl, heteroarylalkyl, cycloalkyloxy, heterocyclicoxy, aryloxy and heteroaryloxy; w is 0, 1, or 2; n is 0, 1, 2, 3, 4, 5, or 6; p is 0, 1, 2, 3, 4, 5 or 6; q can be 0, 1, 2, 3, 4, 5, or 6; r can be 0, 1, 2, 3, 4, 5, or 6; y can be 0, 1, 2, 3, 4, 5 or 6. The compound of general formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein ring B is a 5-membered heteroarylphenyl group. The compound of general formula (I) according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, is a compound of general formula (IIL) or a pharmaceutically acceptable salt thereof. in: Dashed lines indicate single or double bonds; R B1 R B2 R B3 and R B4 They may be the same or different, and each is independently selected from hydrogen atoms or R. B ; L 1 R B G 1 G 2 G 3 G 4 X, Y, R D ,r,R d L 2 R A , n, ring C, R C p and L are as defined in claim 1. The compound of general formula (I) according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein XY is selected from OCH2, CH2OCH2, OCH2CH2, NHC(O), NHCH2 and N(CH3)CH2. The compound of general formula (I) according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, is a compound of general formula (IIIL) or a pharmaceutically acceptable salt thereof. in: R C1 Selected from hydrogen atoms or R C ; R 6A Selected from hydrogen atoms or R 6 ; m is 0, 1, or 2; m1 is 0, 1, 2, 3, 4, 5 or 6; L 1 R B1 R B2 R B3 R B4 R 4aa R 6 G 1 R d R A n, R C And L as defined in claim 3. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein Selected from Where R A and n as defined in claim 1. The compound of general formula (I) according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R 6A Selected from hydrogen atoms, halogens, C 1-6 Alkyl, 2- to 6-membered heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 alkoxy, cyano, amino, hydroxy, 3- to 8-membered cycloalkyl, 3- to 8-membered heterocyclic, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl, wherein the C 1-6 Alkyl, 2- to 6-membered heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 The alkoxy, 3- to 8-membered cycloalkyl, 3- to 8-membered heterocyclic, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl groups are each independently selected from halogens, oxo groups, C... 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, cyano, hydroxyl and C 1-6 It is substituted by one or more substituents in the hydroxyalkyl group. The compound of general formula (I) according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein G 1 Let N be the number of elements in the array. The compound of general formula (I) according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein R d Selected from hydrogen atoms, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, 3- to 8-membered cycloalkyl, 3- to 8-membered heterocyclic, 3- to 8-membered cycloalkyl C 1-6 Alkyl, 3 to 8-membered heterocyclic C 1-6 Alkyl, 3- to 8-membered cycloalkyl C 2-6 alkynyl and 3 to 8-membered heterocyclic C 2-6 alkynyl group, the C 1-6 Alkyl, 3- to 8-membered cycloalkyl, 3- to 8-membered heterocyclic, 3- to 8-membered cycloalkyl C 1-6 Alkyl, 3 to 8-membered heterocyclic C 1-6 Alkyl, 3- to 8-membered cycloalkyl C 2-6 alkynyl and 3 to 8-membered heterocyclic C 2-6 The alkynyl group may optionally be substituted with one or more R* groups, wherein R* is as defined in claim 1; and / or R B1 Selected from hydrogen atoms, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyl alkyl, 3- to 8-membered cycloalkyl and 3- to 8-membered heterocyclic groups; and / or R B2 R B3 and R B4 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl and C 1-6 Halogenated alkyl groups; and / or R C1 Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyl alkyl, cyano, 3- to 8-membered cycloalkyl or 3- to 8-membered heterocyclic groups; and / or L 1 It is methylene or cyclopropyl. The compound of formula (I) according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein each R A They may be the same or different, and each is independently selected from halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyl and cyano groups, or two R groups on the same atom A Or two R atoms on different atoms A Together with the attached atoms, it forms a 3- to 8-membered cycloalkyl or 3- to 8-membered heterocyclic group, wherein the 3- to 8-membered cycloalkyl or 3- to 8-membered heterocyclic group is optionally reacted with one or more halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyl and cyano substitutions. The compound of general formula (I) according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein L is a 3- to 8-membered cycloalkyl group, said 3- to 8-membered cycloalkyl group optionally converted by one or more halogens, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, =CR 62 R 63 C 1-6 Haloalkyl, C 1-6 Hydroxyl and cyano substitution, R 62 and R 63 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl; or L is Ring W 1 For optional use by one or more R F Substituted nitrogen-containing heterocyclic group, ring W 2 It is a cycloalkyl or heterocyclic group, R W3 For hydrogen atoms or R # w4 is 0, 1, 2, 3 or 4, R F R # R 11 and R 12 As defined in general formula (I); or L is selected from The compound or its pharmaceutically acceptable salt, wherein the compound is selected from: A compound of general formula (IA) or a salt thereof, in: G 1 G 2 G 3 G 4 X, Y, R D ,r,R d R 2 L 2 Ring A, R A , n, L 1 R R , ring C, R C p, ring B, R B And q as defined in claim 1. The compound of general formula (IA) according to claim 13, or a salt thereof, is selected from the following compounds: A method for preparing a compound of general formula (I) according to claim 1, comprising: The compound of general formula (IA) or its salt undergoes a condensation reaction with LC(O)OH or its salt to give the compound of general formula (I) or its pharmaceutically usable salt. in: G 1 G 2 G 3 G 4 X, Y, R D ,r,R d R 2 L 2 Ring A, R A , n, L 1 R R , ring C, R C p, ring B, R B And q as defined in claim 1. A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 12, and one or more pharmaceutically acceptable carriers, diluents or excipients. Use of the compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition according to claim 16 in the preparation of a medicament for inhibiting RAS mutant proteins. Use of the compound of any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of claim 16 in the preparation of a medicament for the treatment and / or prevention of diseases or conditions mediated or dependent on RAS mutant proteins. The use of the compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition according to claim 16 in the preparation of a medicament for treating and / or preventing tumors; wherein the tumors are preferably selected from thyroid cancer, head and neck cancer, esophageal cancer, gastric cancer, lung cancer, liver cancer, kidney cancer, pancreatic cancer, gallbladder cancer, brain cancer, skin cancer, testicular cancer, bile duct cancer, colorectal cancer, urothelial carcinoma, bladder cancer, breast cancer, ovarian cancer, uterine cancer, endometrial cancer, cervical cancer, prostate cancer, leukemia, lymphoma, myeloma, appendiceal cancer, melanoma, sarcoma, and glioblastoma; more preferably selected from gastric cancer, pancreatic cancer, colorectal cancer, and non-small cell lung cancer.

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